Cytokinetics Inc Q1 FY2022 Earnings Call

Good afternoon. And welcome, ladies and gentlemen, to Cytokinetics' First Quarter 2022 conference call. At this time, I’d like to inform you that this call is being recorded and that all participants are in a listen-only mode. At the request of the company, we will open the call for questions-and-answers after the presentation. I will now turn the call over to Diane Weiser, 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, President and Chief Executive Officer, will begin with a brief overview of the quarter and recent developments. Fady Malik, EVP of R&D, will then provide updates related to omecamtiv mecarbil and aficamten; Andrew Callos, EVP and Chief Commercial Officer, will discuss commercialization planning activities for omecamtiv mecarbil and our franchise strategy related to aficamten; Stuart Kupfer, SVP and Chief Medical Officer, will provide an update on reldesemtiv. Robert Wong, VP and Chief Accounting Officer, will provide a financial overview for the past quarter. And Ching Jaw, SVP and Chief Financial Officer, will discuss our financial outlook and corporate development strategies. Finally, Robert Blum will provide closing comments and review expected key milestones for 2022. 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 first quarter 2022 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, Diane, and thanks again to everyone for joining us on the call today. We had a productive quarter, and we're moving closer toward our planned transformation to become a fully integrated research development and commercial company. Most notably, our NDA for omecamtiv mecarbil was accepted for filing by the FDA with a PDUFA date of November 30, 2022. Since then, we've had ongoing interactions with the FDA to address specific queries, and the team at Cytokinetics has worked diligently to prepare timely responses to their requests. We will soon meet with the FDA in a mid-cycle review of our application, as is customary. For the most part, queries to date have been administrative or have supported additional requested analyses. The NDA acceptance was also a key derisking milestone that ungated certain spending related to our measured commercial readiness activities. We've continued to build our teams and create a commercial infrastructure to support the potential approval of omecamtiv mecarbil in the near term, as well as the potential commercialization of aficamten following the completion of our pivotal trials, SEQUOIA-HCM and subsequently its potential FDA submission for approval. We're pleased to be attracting very high-caliber talent, and we're hiring individuals who bring with them great experience and expertise. From a clinical perspective, we shared additional data from two new analyses from GALACTIC-HF at ACC that add to our understanding of both the clinical and pharmacoeconomic impacts associated with the addition of treatment with omecamtiv mecarbil when added to standard of care therapy. We continue to believe that omecamtiv mecarbil can make a meaningful impact on important outcomes when added to standard care and for the right patient. We believe that clinical opportunity affords a solid business case for establishing commercial capabilities, as well as to serve our cardiac muscle franchise objectives. Building on that theme, during the quarter, we also made significant advances in the development program for aficamten, including the opening of enrollment in SEQUOIA-HCM, the pivotal Phase 3 clinical trial of aficamten in patients with symptomatic obstructive HCM. As Fady will elaborate, site startup and activation activities are progressing on pace, as is the screening and enrollment of patients. Following the positive results from Cohort 3 of REDWOOD-HCM shared during the quarter, we're now enrolling patients whose background therapy includes disopyramide into SEQUOIA-HCM, a key milestone and opportunity to include the sickest patients in need of new therapeutic options. We've also opened enrollment in Cohort 4 of REDWOOD-HCM for patients with non-obstructive HCM, an important patient segment representing approximately one third of the prevalent HCM patient population. At the end of the first quarter, we remained on strong financial footing, with over two years of projected cash runway even as we expect our operating expenses may increase next year. This year will be a transformational one for the company with key milestones across our pipeline, and we're moving closer to making good on our promise to bring forward new muscle directed medicines for patients with diseases of impaired muscle function. And with that, I'll turn the call over to Fady please.

Thanks, Robert. While the NDA is under review by FDA, we are continuing to pursue additional learnings from GALACTIC-HF. Last month at ACC, we presented new data from an analysis of GALACTIC-HF showing that the effect of treatment with omecamtiv mecarbil versus placebo on the primary outcome was similar in hospitalized patients and outpatients, indicating that omecamtiv mecarbil similarly reduced the risk of the primary outcome, both when initiated in hospitalized patients and in outpatients. Additionally, this analysis showed that starting treatment with omecamtiv mecarbil in the hospital was both safe and well tolerated, speaking to the ability to initiate omecamtiv mecarbil in these patients who are at greater risk for rehospitalization and cardiovascular death. Importantly, recent published studies have shown that medication started while patients are in the hospital have some of the best long-term adherence, making these results more significant. Additionally, at ACC, we presented the full results from METEORIC-HF evaluating the effect of 20 weeks of treatment with omecamtiv mecarbil compared to placebo on exercise capacity. There was no effect on the primary endpoint, which was the change in peak oxygen uptake or peak VO2, as measured by cardiopulmonary exercise testing from baseline to week 20. This study joins other studies of heart failure therapies that have shown a positive impact on cardiovascular outcomes but have not been successful in impacting exercise performance in patients with heart failure. These data further suggest that it may be particularly challenging to impact exercise capacity in this patient population, possibly due to comorbidities or deconditioning associated with heart failure. The results from METEORIC do add to the safety profile of omecamtiv mecarbil, showing that under conditions of peak exercise, adverse events, including major cardiac adverse events are similar between the treatment arms. As we stated previously, we do not expect the results from METEORIC-HF to have an impact on the NDA currently under review by the FDA. Also during ACC, new guidelines were issued by ACC, AHA, and HFSA including updates to treatment options for treating patients with heart failure and reduced ejection fraction. In particular, the guidelines outline the characteristics of patients with persistent or worsening heart failure, whose risks of adverse cardiovascular outcomes are high. Also, GLP-II inhibitors were added as a fourth class of medication within guideline directed medical therapy, or GDMT. We believe these updates augur well for the possibility of future inclusion of omecamtiv mecarbil and guidelines as an add-on therapy to standard of care therapy, particularly in patients with persistent or worsening heart failure who remain symptomatic and whose risks are elevated despite being on GDMT. We continue to prepare for the potential approval of omecamtiv mecarbil. On the medical affairs side, we doubled the size of our therapeutic medical scientists team, hired a field director, and began recruitment for our managed healthcare medical sciences team. I'm also pleased to announce that we have two abstracts from GALACTIC-HF accepted for presentation in the late-breaking science session at the European Society of Cardiology Heart Failure 2022 taking place in Madrid from May 21 to May 24. One is an analysis of the effects of omecamtiv mecarbil on patients with lower blood pressure, and the other is an analysis in patients with tricuspid regurgitation as baseline. We look forward to re-engaging with our European colleagues that we've not seen for some time given the pandemic. Turning now to aficamten. As Robert mentioned, it was a productive quarter for this multifaceted development program. Notably, we opened enrollment in SEQUOIA-HCM, the Phase 3 pivotal trial of aficamten in patients with symptomatic obstructive HCM. SEQUOIA-HCM will assess the potential of aficamten to improve exercise capacity, symptoms, and functional class in patients with obstructive HCM and will employ a personalized dosing scheme to maximize the potential treatment effect and enable patients to reach their target dose quickly. Following the positive results of Cohort 3 of REDWOOD-HCM, we're now including patients whose background therapy includes disopyramide. Sites across the U.S. are actively screening and enrolling patients, and many others are conducting startup activities. We expect sites outside of the U.S. to begin screening patients in early Q3. Additionally, during the quarter, we opened enrollment in Cohort 4 of REDWOOD-HCM for symptomatic patients with non-obstructive HCM. Cohort 4 will enroll 30 to 40 patients in an open-label fashion to escalating doses of aficamten of 5-10 or 15 milligrams as informed by echocardiography. While the primary objective is the safety and tolerability of aficamten, we're also evaluating the effect of aficamten on left ventricular ejection fraction, New York Heart Association Functional Class on Cardiac Biomarkers including NP pro-BNP. We expect the data from this cohort to inform the design and conduct of a potential pivotal Phase 3 clinical trial in non-obstructive HCM following the completion of Cohort 4. To remind you, last quarter, we announced our plan to begin a second Phase 3 clinical trial of aficamten in obstructive HCM in the second half of this year. We received many questions about this planned trial, so let me provide some clarification. First, this trial was not requested by the FDA, and SEQUOIA-HCM remains the sole pivotal Phase 3 trial with which we believe we would submit for approval of aficamten. Second, the goal of this additional Phase 3 trial is to better understand and position the use of aficamten relative to standard of care therapy. As such, it will not be a head-to-head trial against mavacamten. We believe we have an opportunity to advance the field with a next-in-class drug candidate by pursuing important scientific questions. This trial, along with others we may conduct, may address questions important to understanding the use of a therapy with a new mechanism of action in patients with a spectrum of disease severity and background therapy. Often these trials await initial drug approval, but we're confident in aficamten and believe it's advantageous to embark on the study sooner. We know there's greater interest in the design of this trial, and we plan to share more detail later this year. Towards our goal of sharing longer-term data on the treatment of aficamten in patients with obstructive HCM, we're pleased to announce that the first data cut from the open-label extension of REDWOOD-HCM will be presented in a late-breaking science session at the Heart Failure 2022 Meeting in Madrid. This interim look will include data from up to six months of treatment with aficamten. Patients continue to be treated with aficamten in the open-label extension, and further analyses of these data are still forthcoming later this year. Looking beyond aficamten, we're pleased to see that the FDA recently approved mavacamten for the treatment of patients with obstructive HCM, making it the first medical therapy for HCM to be approved by the FDA. We'd like to offer our congratulations to the teams who worked to bring this new mechanism therapy to patients and take pride in this milestone given our discovery role for the program. This is a milestone for patients with HCM who've been in desperate need for new therapies to address the heavy burden of symptoms they endure. We also believe this milestone approval will provide context for our own potential differentiation of aficamten following results from our pivotal trial.

Thanks, Fady. During the first quarter, we continued to build out our commercial capability as an organization. We began hiring our first line field-based sales force leaders, as well as filling key positions across marketing, market access, sales, and commercial operations. We've selected a patient support service partner, continued payer interactions, and activities supportive of deploying our field force. As we continue engaging with payers, we are mindful of the critical importance of the potential value proposition for omecamtiv mecarbil. Recently at ACC, we presented data from a healthcare resource utilization analysis from GALACTIC-HF showing that among a subgroup of patients, treatment with omecamtiv mecarbil reduced resource intensity measured by total days in the hospital. The estimated potential cost offset was $3,085 or 19% per patient, and 99% of the cost reductions were due to heart disease or hospitalization among those treated with omecamtiv mecarbil. Of course, there are limitations to these data as their relevance will be payer-specific. However, if we consider the payment reduction that hospitals face for 30-day readmission for Medicare patients, and the fact that the prevalence of heart failure is increasing, this potential reduction in hospitalizations and their associated costs underscores the types of potential economic value propositions for omecamtiv mecarbil that we will continue to assess to inform strategies. Also during this quarter, we signed a master supply agreement for drug supply, initiated several major digital system programs, including enterprise resource planning and serialization, and hired key supply chain leadership roles. We also completed a risk assessment of our end-to-end supply chain and advanced appropriate mitigation actions. As we have said, our growing cardiovascular commercial infrastructure supportive of the launch of omecamtiv mecarbil will be leveraged for the future potential commercialization of aficamten. With increased awareness in the market of HCM and the clinical utility of cardiac myosin inhibitors, we are confident in the opportunity we have for the future potential launch of our next-in-class therapy with key properties that may impact ease of titration, reversibility, and the ability to reach target concentrations rapidly. We look forward to leveraging our commercial organization and synergies within the treatment community. And with that, I'll turn the call over to Stuart to provide an update on reldesemtiv.

Thanks, Andrew. In the first quarter, we continued enrolling patients in COURAGE-ALS, the Phase 3 clinical trial of reldesemtiv in ALS. Enrollment has been progressing well, with over 70 centers activated in the US, Canada, Australia, and Europe, and more than 150 patients enrolled. Conducting rigorous and disciplined clinical research is essential to our mission. We are pleased to have enrolled the most ALS patients into recent clinical trials than any company, even before COURAGE-ALS, which is planned to enroll 555 patients. The primary endpoint of the trial is a change from baseline to 24 weeks in ALS-FRS, an endpoint being clinically relevant and both FDA and EMA guidances to evaluate a treatment effect on function and daily activities in ALS. The main secondary endpoint is a combined assessment of function and survival, which is a joint rank test of ALS-FRSR total score, tied to the onset of respiratory insufficiency and survival time up to 24 weeks. Other secondary endpoints include change from baseline to 24 weeks for vital capacity, the patient-reported outcome questionnaire ALS-40, and bilateral handgrip strength. Reflective of our focus on patient centricity, we designed COURAGE-ALS with important input from patients and caregivers to optimize the patient experience and reduce the burden, including many remote visits. Additionally, to ensure patients can continue therapy with background medicines, patients who are currently taking stable doses of Riluzole and/or Edaravone are permitted to enroll, and the randomization is stratified accordingly. We also plan to provide continued access throughout to reldesemtiv to patients who complete COURAGE-ALS in an open-label extension trial. Furthermore, patients in COURAGE-ALS, as well as patients who participated in our prior ALS trial, will have the opportunity to enroll in a managed access program developed with the objective to ensure safe, ethical, and equitable access to reldesemtiv. In face-to-face meetings with investigators and patient advocates, we have received enthusiastic support for the patient-friendly protocol in COURAGE-ALS, which was built on the solid foundation of our large and robust Phase 2 trial FORTITUDE-ALS. Later this year, we expect the data monitoring committee to conduct the first interim analysis in the COURAGE-ALS trial, which will assess for futility and is triggered 12 weeks after approximately one-third of the planned number of patients is randomized. A second interim analysis will also assess for futility, and there will be an option for an increase in total enrollment if necessary to augment the statistical power of the trial. ALS is a devastating disease, and no one knows that better than patients and their caregivers. They are desperate for new options and therapies. It is our mission to bring forward a new therapeutic option through high-integrity research and diligent investigation. And with that, I'll turn it over to Robert Wong.

Thanks, Stuart. We ended the first quarter with approximately $686 million in cash and investments. Our revenues in Q1 2022 came from Astellas to co-fund COURAGE-ALS. Our first quarter 2022 R&D expenses increased to $45.9 million from $31.6 million in the first quarter of 2021, primarily due to increases in spending on our cardiac myosin inhibitor program, our new headquarters facility, and our skeletal muscle program. More than 55% of our R&D expenses were attributable to our cardiovascular program. As expected, given activity for the cardiac myosin inhibitor program and the remainder of our expenses were attributable to our skeletal and early research activities. Our first quarter 2022 G&A expenses were $33.1 million, up from $15.6 million in Q1 2021 due to higher commercial readiness spending and higher personnel-related costs, including stock-based compensation. And now Ching will review our financial outlook and corporate development strategies.

Thanks, Robert. Our end of the quarter cash balance of approximately $686 million is inclusive of the $200 million in payments we received from Ji Xing and Royalty Pharma from the transactions announced in December last year and January of this year, respectively. Our balance sheet could be further bolstered by our deal with Royalty Pharma, which affords us access to long-term capital of up to an additional $300 million, subject to certain conditions, primarily to support the potential commercialization of omecamtiv mecarbil and further development of aficamten. Our approach to building a commercial infrastructure will remain prudent with spending time to key derisking milestones. Given our plans to only hire our sales force after potential NDA approval of omecamtiv mecarbil, we expect a slower ramp-up in commercial spending in 2022. If only omecamtiv mecarbil receives approval in late 2022, we expect a more significant post-approval related increases in spending in 2023. Our corporate development strategy remains focused on partnering and longer-term strategies of sensibly building our organization. During the quarter, we continued business development interactions focused on potential partnerships in Asia and Europe. First, we are seeking a potential partner to facilitate the launch of omecamtiv mecarbil in Europe as we focus on our own U.S. launch. Having a partner to commercialize omecamtiv mecarbil in Europe could afford an on-ramp for us to build our own capabilities in Europe in order to support the future commercialization of aficamten ourselves. In Japan, we are looking to partner both omecamtiv mecarbil and aficamten together with a partner to commercialize both potential medicines, similar to how we partnered with Ji Xing in China. We have a history of strong deal-making and look forward to continuing these interactions with potential partners with the objective to close one or more deals this year. And with that, I'll turn the call back over to Robert Blum.

Thank you, Ching. So as you heard, we began 2022 with important progress across our late-stage pipeline, as well as impressive growth across our organization to support the potential approval of omecamtiv mecarbil later this year. We recently surpassed 300 employees, and I'm pleased with the caliber of talent and the expertise we're building across the organization. Candidates are excited to join our team given our leadership in muscle biology and the promise of our potential medicines. I want to take this opportunity to thank our employees for all that they're doing to build a next-grade biopharmaceutical company. We recently conducted a comprehensive employee survey and had 98% employee engagement, underscoring our highly committed employees who care deeply about doing impactful work on behalf of patients. During the quarter, we also continued intensive work towards our goal of advancing earlier stage drug candidates, including CK-136, our cardiac troponin activator, as well as other muscle directed compounds into IND enabling studies. Our cardiovascular pipeline continues to expand with novel mechanism drug candidates leveraging over two decades of our pioneering leadership in muscle biology and pharmacology, and more to come on those programs soon. At the leadership level, we recently announced changes to our board of directors, Dr. Pat Gage who served as our Chairman of the board since 2010, retired from the board. This was a planned transition announced over a year ago. His retirement was a personal decision, and he departs with our utmost respect and admiration. We thank him for his many years of service to our board. Upon Pat’s retirement, Dr. John Henderson was named the new chairman of the board. John has served as a member of our board since 2009, and we're confident he will lead with discipline and a strong vision for the company in his new position as Chairman. Additionally, we appointed Dr. Bob Harrington to our board. Bob's appointment follows the resignation of Rob Califf from our board, which was prompted by his being named FDA Commissioner. Like Rob, Bob is a cardiologist. Bob is also Chair of Medicine at Stanford and has a distinguished academic career, bringing broad experience having overseen dozens of global cardiovascular clinical trials. We're very pleased to welcome Bob to our board. Finally, as Ching elaborated, our recent deal with Royalty Pharma not only extends but also expands our partnership and provides ample runway to execute on our commercial and clinical plans in a prudent yet purposeful manner. As we continue to execute against our Vision 2025, our ability to monetize our pipeline in order to realize our ambitious goals remains mission-critical. This newer deal is consistent with our corporate development strategies to affordably enable our transformation to a commercial stage company, while also continuing to accelerate our development plans. Now, I'll recap our key milestones for 2022. For omecamtiv mecarbil, we expect to launch omecamtiv mecarbil in the U.S. pending potential FDA approval in Q4 2022. For aficamten, we expect to continue enrolling patients with obstructive HCM in SEQUOIA-HCM throughout 2022. We expect to continue enrolling patients with non-obstructive HCM in Cohort 4 of REDWOOD-HCM, and we expect to begin a second Phase 3 clinical trial of aficamten in obstructive HCM in the second half of this year. As you heard from Fady, we expect to share data from REDWOOD-HCM OLE, the open-label extension study about aficamten at the heart failure 2022 meetings later this month, on May 23, 2022. For CK-136, we expect to reactivate that development program this year. For reldesemtiv, we expect the data monitoring committee to conduct the first interim analysis from COURAGE-ALS in the second half of this year. For our ongoing research, we expect to advance new muscle directed compounds and to conduct IND enabling studies for one to two potential drug candidates. And operator, with that, we can now open up the call to questions please.

Thank you. Your first question comes from Carter Gould of Barclays. Your line is open.

Good afternoon, guys, hey, great. Maybe good afternoon, maybe to start with for Robert and Fady. Probably an appropriate opportunity to get you guys to comment a bit on the mavacamten label and pricing and specifically, as you think about implications for differentiation, and the market opportunity? I know Robert, you never kind of explicitly guided on pricing assumptions, but it does appear directionally higher than we and much of the street had had expected. We'd love to get your thoughts on those topics.

Sure. So I'll start and maybe turn to Fady. And also we should ask Andrew to comment, especially as your question pertains to pricing. Firstly, we want to congratulate BMS and all the colleagues at MyoKardia for this approval, but also the HCM patients, the clinical investigators, the advocacy groups, and everyone else that participated. And that includes Cytokinetics scientists who conceived of the therapeutic hypothesis for cardiac myosin inhibition and who participated in the discovery of mavacamten. This is a meaningful milestone for the fact that it's the first drug approved with an indication of obstructive HCM. The data from EXPLORE are surely compelling. With that said, as others have commented, the label is now in the public domain. There are things about that label that we think make sense and things about that label that enable a next in-class opportunity to potentially demonstrate differences. That's why we're doing SEQUOIA-HCM. We hope SEQUOIA-HCM will elaborate on what could be next-in-class properties purposely engineered into aficamten long ago. You asked about pricing. Yes, I think the pricing did come in higher than expected consensus. We were within that consensus, expecting price to be different. With that said, pricing is now coming in comparably to surgical interventions. When you consider the number of echoes that need to be performed to get to a steady state target dose and a maintenance program for mavacamten, the costs are even excessive. We expect BMS knows what they are doing. They have done their payer research and their work around pharmacoeconomics. Despite what ICER came in with, I expect BMS understands what the market clearing price will be. From the standpoint of patient assistance and contracting, there are programs that will be elaborating on how that could still result in lesser net costs to patients and assist in reimbursement. I think this is all still to be playing out in connection with what I'm sure will be sensible commercial launch plans that BMS is implementing. With that, I'll ask Fady or Andrew if there's anything further they want to elaborate?

Well, maybe I'll just expand a little bit on aficamten and how we have developed it and what we think it may provide in terms of convenience for patients and safety and so forth. You can sort of do your own comparison. With aficamten, the way SEQUOIA is designed, dose escalation should be complete within six to eight weeks. We don't anticipate those interruptions if yes, or less than 50, as long as they're greater than 40, but merely dose down titration. Hopefully, those data from SEQUOIA, as well as from the ongoing open-label extension, would support a simple escalation scheme that's completed within six to eight weeks. Aficamten was engineered to avoid drug-drug interactions, and to date, we haven't uncovered any significant drug-drug interactions with aficamten. We've shown the reversibility of effect and data that we've presented from REDWOOD, which I think enables its type tradability and also provides a means to safely escalate or de-escalate the dose. Those are the things I would highlight, and as well as the conduct of SEQUOIA, we're studying it in both monotherapy with other drugs like beta blockers, calcium channel blockers, dual therapy with those drugs or with disopyramide and beta blockers as background therapy. We think we have a fairly good understanding of how it performs in those various different conditions.

Andrew, anything you want to add?

This is maybe very quickly on pricing, I won't say much about obviously BMS’s strategy, more than as Robert stated, maybe came in slightly higher than we were expecting. It'll be interesting, and we'll obviously look how the market reacts meaning payers. If there are more controls, they would put in place prior things like prior off the label, or step that is through beta blockers or calcium channel blockers. Those types of things we'll see. It did come in flat pricing, meaning every dose is the same price, which is as we expected. There could be further costs in terms of support programs and room to negotiate. I think these are all the factors that likely went into it. But we have some time to continue to evaluate the market and see how we net out from a labeling point of view as we decide our pricing in the future.

Thank you.

Thank you, Carter.

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

Hi, I'm Troy in for Jason, thanks for taking the questions. The first one of couple clarification questions. I’m confused by Fady’s comments about the second obstructive HCM Phase 3. He said if it's not going head-to-head against mavacamten but against a drug with a novel mechanism. Can you just clarify that it? Presumably it's an approved drug?

That's not exactly what he said. But maybe he can elaborate.

Okay. What I said it would be a standard of care therapy. So I didn't elaborate on the design of the second trial. I just said that it wouldn't be against mavacamten. It could be against standard of care or other aspects of the disease.

Got it. That make sense. Is this finalizing the trial design? Is that all this gating just starting that trial now?

I wish starting trials were that easy. No, once we finalize the trial design, the other operational things such as IRB submissions and regulatory submissions and so forth. We will ultimately have a regulatory interaction as well. There are a few things ahead of beginning enrollment. But we've got all those under control.

Okay, great, and on COURAGE-ALS, you mentioned increasing the enrollment size. Can you do that at both of the interims? Can the trial be stopped early for efficacy?

Hi. This is Stuart Kupfer. Thanks for the question. So the first interim analysis is for futility only. There's not an option for upsizing the trial. But that is an option for the second interim analysis. In terms of stopping for efficacy, the second run-out essentially has quite a broader range that includes futility and potentially stopping for superiority. But yeah, that's a very high bar. So that's not something we're necessarily counting on.

Okay, thank you.

Thank you.

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

Hey there. Good afternoon, everybody. I also wanted to stick with COURAGE. So very encouraging the enrollment that you're seeing but also a bit disquieting, because the underlying indication that the demand remains high. I just wanted to focus on the interims as well. Are you disclosing or can you remind us what the alphas spend is for each of the interim analyses and overall, what the hurdle is?

Right, we haven't really disclosed those details. What I think we can say is that for this first interim analysis for futility, it's not a really high bar to continue the trial. So we're confident that we'll be proceeding past that interim analysis.

What we've learned is that the reldesemtiv treatment arm would have to do worse than the standard of care for us to meet the futility threshold for the first interim. That's a low bar for what we already know. The second interim does provide for early stopping for futility or otherwise allows us to increase the size if we wanted to amplify a signal observed, albeit that would be blinded to us. The data monitoring committee will determine that. We have not disclosed any of the alpha spend.

Nope, that's just to be clear for futility. There never is alpha spent. So there's no alpha spend on any of the futility analysis solely with regards to efficacy if you decide to include that.

Got it. Thank you for the clarification. And then just on omecamtiv, you said it's mostly administrative back and forth with the FDA right now. Do you consider any of the back and forth rate limiting at this moment? Additionally, with the METEORIC data, any learnings that you would point to that allow for the potential of tweaking the population or the protocol? Or is that potential path closed at this point?

I'll take the first one and maybe ask Fady to speak to the second one. Regarding your question about the back and forth in interactions with the FDA, I don't consider any of them to be rate limiting or to affect the timeline for review and approval. These interactions are customary for an application of the sort that we submitted. Therefore, I think we remain on the same timeline.

The same question with regards to METEORIC. I don't think that we haven't really identified a subgroup in the METEORIC population where we could confidently say that there is a large treatment effect that would warrant redoing the trial per se. That said, within METEORIC, we did enroll very sick patients. They were kind of the opposite of what we've enrolled in GALACTIC. One could ask if you were able to conduct the trial in a much sicker patient population, might you see an improvement in exercise capacity? I think it’s still an open question, but it's unlikely we'll pursue it; there are a lot of operational challenges.

Of course. Thanks for the added color, guys.

Thank you.

Thanks, Joe.

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

This is Amy on for Akash. Thanks so much for taking our question. Just a couple. If we look at the mavacamten label, it seems like the benefit from mavacamten is smaller in patients on background beta blocker compared to those who weren't? Why do you think we're seeing this phenomenon? Can it be that patients on beta blockers at baseline may have lower LVF to begin with, which could potentially limit mavacamten's ability to up-dose? And where do you think aficamten could potentially differentiate?

These are some of the observations that came out when these data were presented and published. Maybe I'll ask Fady if he wants to comment on that.

I mean, generally, we can comment on the challenge of beta blockers and trials of exercise performance. METEORIC also had almost 90% of the patients on beta blockers. They have two different effects, right? They limit the amount that you can increase your heart rate, which is important to increase in cardiac output, and they also act on skeletal muscle and decrease its ability to exercise as well. In the context of hypertrophic cardiomyopathy, mavacamten demonstrated improvements in exercise capacity in patients with beta blockers albeit the effects were attenuated, not surprisingly, because of the combination of those two therapies. The real question to ask is, in the context of using a cardiac myosin inhibitor, is beta blocker therapy really needed in HCM? Ultimately, is that something that physicians need to institute in their patients? Might they maximize their treatment benefit and their quality of life eventually by substituting a myosin inhibitor for a beta blocker? Those are important research questions as you can imagine, and I think answers will unfold as time goes on.

Great, that's super helpful. And then another one, mavacamten seems to show greater benefit in NYHA class 3 patients in EXPLORE. How do you think aficamten can compare relatively to mavacamten in these patients?

Again, I hate to say, we're not doing a comparative trial, so it's going to be very hard to compare exact numbers from one study to the other, given the populations will be somewhat different. Generally, I think sicker patients will generally achieve greater benefits; they have a greater symptomatic burden, greater exercise burden, and there's more room for them to improve. It's not surprising if you will that the more severely affected patients have a greater treatment effect.

Okay, got it.

It's for aficamten.

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

Hello, Robert. Hey, Robert. Thanks for the question, guys. Just a couple from me, the first on mavacamten. So, Robert, I'd love to know now that we have a price tag in the marketplace for mavacamten. And if I'm just running some basic math here, when I look at consensus peak, mavacamten currently has peaked around $3.5 billion. And mavacamten, the best I can tell, is closer to around $1.5 billion. So that's about $5 billion. And those are worldwide numbers. But now that we have priced in the market, just using that 90k price tag and the number you have in your slides for 190k obstructive patients symptomatic just in the U.S. Obviously, you get two tabs here that are much larger, even if you assume a 40% gross to net and 80% compliance. Just curious here, how are you thinking about TAM now that there's a price in the marketplace? How TAM can mature here for this particular disease?

If you're asking us if there appear to be discrepancies between those underlying assumptions and the consensus estimates, I think there are, and I think you've pointed that out already in some of your notes. Now that we have a price as set by BMS, it's an opportunity for analysts and investors both but also for us at Cytokinetics to consider how we think about this market opportunity. We will, but in line with data. We're still enrolling patients in SEQUOIA. It's premature for me to be elaborating on what I mean by that. In time, I think this will all play out. We continue to believe that a next-in-class opportunity can become the category leader.

Do you think there's potential here for this to be a $10 billion-plus market worldwide?

I'm not going to speak to that. I do think that where this market ultimately will go will benefit from what will be category expansion, patients who are not currently diagnosed and treated getting diagnosed and treated. Ultimately, this mechanism of action should hopefully translate beyond obstructive HCM to non-obstructive disease, including segments of patients with hap-path. Ultimately, I think there's very meaningful opportunity for this to be a big business.

Okay. And then just a quick one, just on the REMS and how you guys are thinking about base case here for Cytokinetics and aficamten. I know that it's early, and you don't have Phase 3 data yet. But based on what you've seen from the profile for aficamten in REDWOOD in the shorter PK/PD, the shorter half-life, what is your base case? Do you think that you can, is there a possibility here that you don't have a REMS?

Yes. Here again, I'm not going to make a comparative statement. But as we think about aficamten as an independent drug development program and for the safety data we've already seen in REDWOOD-HCM, one wouldn't necessarily expect REMS. There are things that we have to demonstrate in SEQUOIA-HCM in order to ensure that. We're approaching SEQUOIA-HCM with the goal of elaborating on what could be the next-in-class properties that could afford a safety profile that would potentially not require REMS.

Salim, I think it's also important to remember, by the time we hopefully come to market, this will no longer be a new drug class, and physicians will be more familiar with the use of a cardiac myosin inhibitor. Obviously, there will be differences between different drugs, and in the need to educate on those differences. But it's not a first-in-class entry. That may also temper the need for REMS.

Super helpful. Thanks so much, guys.

Thank you, Salim.

Your next question comes from the line of Madhu Kumar of Goldman Sachs; your line is open.

Hello. This is Omar on for Madhu. So we have a couple of questions. First, what kind of data should we expect from the REDWOOD-OLE at Heart Failure 2022 in May? The standard endpoints and average time to follow-up? And then remind us how the echo monitoring works in both REDWOOD-OLE and SEQUOIA-HCM? How are they similar or different from prior and ongoing trials of under myosin and progress in oHCM? Then I have a second question after that.

Sure. We don't want to do anything to jeopardize the presentation of the data by elaborating on what you should expect. This is a study that now enables a longer durability effect to be observed. Our goal is to demonstrate that with aficamten, one can achieve a continuing effect. You'll see data pertaining to the use of aficamten as Fady elaborated, out to six months. I’ll turn to Fady now if there's anything more he wants to add.

I think you can expect the kinds of things we presented in the past, which have to do with gradients and EF and safety NYHA class, things like that. We're likely to focus on the same themes we've elaborated on in prior presentations. Your second part was related to echo monitoring. The general scheme in all our trials is the same. Patients come in at least every two-week basis for an echo and potential to be escalated to the next dose. In the OLE right now, we're restricted to doses of 5-10-15 milligrams. In SEQUOIA, the top dose is 20 milligrams, so doses of 5-10-15 and 20. OLE is only restricted due to the need to amend the protocol. The dosing is quite similar among all the trials that we're conducting.

I'll add an additional data set where we'll be capturing data in OLE as well as SEQUOIA, which is cardiac MR data, evaluating cardiac structure, function, and fibrosis. So that will give us an opportunity to evaluate for reverse remodeling.

But it will be premature to say that at this upcoming congress.

Great. And then second question, what kind of patient subsets in HCM will be most amenable to myosin inhibitor given the history of the class?

What types of patients would be most amenable to benefiting from a myosin inhibitor?

In nHCM? Okay. I was trying to parse it out. Well, there are a few things that define nHCM patients. One, obviously, is the thickness of their ventricle. The second are biomarkers that indicate a ventricle under stress, like anti-proBNP or troponin. The third is a functional and symptomatic domain, how severe their symptoms are or how impaired their exercise capacity is. An echo showing that you have a thickened ventricle and maybe family history of HCM isn't necessarily adequate for thinking about initiating therapy with the myosin inhibitor or any therapy at this point. Most therapies are being studied in symptomatic or functionally limited patients. That's what I would consider a population that could be studied in future trials.

Great. Thanks for answering the questions.

Thank you.

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

This is Rob on for Yasmeen. A couple of questions for us. The first one is we see that the mavacamten label has shown that the drug might be related to embryonic and fetal toxicity. Do we know if this is a myosin inhibitor class effect, and what work has been done with mavacamten to roll out this toxicity? The second question is regarding the second Phase 3 trial for aficamten, although it's not a head-to-head mavacamten. Are you saying it would be more oriented towards more severe patients who are subject to therapy, and the trial would be somewhat similar to the trial?

Yes. Regarding aficamten, if your question is about potential repro toxicities or any drug-drug interactions, I’ll ask Fady to elaborate on what we know and what we still need to learn.

Sure. We've conducted embryo-fetal toxicity studies with aficamten. They don't indicate any direct toxicity of aficamten on fetal development. Any drug that has the potential to affect the maternal host can, at higher doses, certainly cause fetal toxicity as a secondary effect, but we don't see any direct fetal toxicity. Regarding your second question about the profile of patients in SEQUOIA, we have biased the entry criteria to hopefully enable us to enroll a patient population that is a bit more Class 3, that's a bit more functional.

That's the second trial, the second Phase 3.

The second Phase III will enroll a more severe patient population. However, we're not really commenting on the particular design. I can't really answer your question, but I could certainly have answered the first one. So I'll leave it at that.

Thanks. Got it.

Thank you.

Your next question comes from the line of Dane Leone of Raymond James. Your line is open.

Hi, guys thanks for the question. This is Sean on for Dane. Just since we're at the end of the call here, just a couple of quick ones from us. One, can you comment on the enrollment rate for SEQUOIA to date and how you would expect that to be impacted by mavacamten hitting the market? And then second, just a clarification on your OpEx for the year. You previously guided to upwards of $380 million, but it seems like maybe it could be coming down. Just a clarification there.

Sure. With regard to the first, SEQUOIA-HCM just opened. We are in the process of convening investigator meetings. The U.S. meeting having been held and others to follow. It's premature to comment yet on enrollment. It's probably better to ask how we do it on activations and initiations, and all that looks good, according to plan. I don't know if Fady, you or Stuart, want to add anything to that.

It's too early to give you a sense of how fast it's enrolling since enrollment is early. I will say that investigator enthusiasm has been very high. People are excited about the availability of mavacamten, but the enrollment in SEQUOIA presents a unique opportunity for the patient to advance the field and ultimately have access to aficamten open-label extension. That will be attractive to patients as well. The trial will enroll in regions outside of the U.S. where there is no availability of mavacamten. Ultimately, I think it will enroll quite well.

When we indicated we thought that this study could enroll within about a year, it was with full expectation that mavacamten was going to get approved in the U.S., and the approval doesn't change our view towards that enrollment rate. Your next question was about OpEx. I'll turn to Ching maybe to answer that one, please.

Sure. So you're right. We guided that for the year, we'll expect the cash burn to be in the range of $365 million to $385 million. Of course, the first quarter numbers were lower than if you were to just take that number and divide by 4, but that's not really how we plan for OpEx for this year. We elaborated earlier that we're building our commercial organization and capability based on us achieving certain milestones throughout the year. Naturally, as certain people get hired throughout the year, they're going to carry more cost towards the second half of the year compared to the first half of the year. So, do we expect the quarterly spend to ramp up from the first quarter numbers?

Okay. Great. Thank you.

Thank you.

Your next question comes from the line of Justin Kim of Oppenheimer. Your line is open.

Good afternoon. Hi, Robert. Thank you for taking the questions. Maybe just to elaborate a little bit further on some of the questions already asked. But with the recent approval and labeling of mavacamten seeming to suggest the importance of continued development in additional populations, just curious whether it's reasonable and even prudent to expect further trials even beyond a second study in symptomatic HCM given the fact that there are a number of different populations that could see benefit.

Justin, you attended the American College of Cardiology meetings, and I noticed your presence there. The excitement surrounding this new mechanism could truly enhance treatment for these patients. This enthusiasm is not solely driven by the EXPLORE and SEQUOIA studies. You are correct that there should be additional research, potentially extending beyond what we are currently considering for the second Phase 3 study, whether it occurs before or after approval. We are more optimistic about post-approval studies, based on our timelines. We are already contemplating other research related to aficamten, beyond the two Phase 3 studies that we've mentioned.

Okay. Great. Great. And maybe just one more on the REMS program requiring echocardiography every 12 weeks. Any or maybe more direct thoughts on how the team thinks that may change broadly for myosin inhibitors or specifically for the design of aficamten?

You understand anything we might say right now is speculation for the fact that we're still doing a Phase 3 study. We haven't been requiring the number of echoes as is currently contemplated by the mavacamten label. It does take a couple of echoes to get to a starting dose for aficamten, which can happen within a few weeks, as opposed to a much longer period of time. Therefore, we haven't had any of the dose discontinuations or interruptions. Our expectation is if we continue to develop aficamten the way we have, one shouldn't require the kind of frequent echo monitoring, but that's still to be determined, and we haven't done the trial yet, and we have to demonstrate that with clinical evidence. Fady, I don't know if there's anything more you want to add.

I just think it's going to be looking at the need for continued monitoring in the context of long-term treatment with aficamten and the open-label extension, as well as what emerges from SEQUOIA. The data will inform eventually what the label will look like.

Great. Thanks so much.

Thank you.

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

Hi, this is Pete Stavropoulos on for Charles. Congrats on all the progress this past quarter. One of our questions is what are the plans or expectations for an OMEADCoM? What would you expect the key points of debate to be, especially concerning the burden of disease in patients with ejection fraction less than 30%?

As we've communicated previously, we’re not anticipating an ADCOM for omecamtiv in connection with the NDA as submitted and now on file. That's as was communicated to us by the FDA and as reflected in our public announcement. That's not to say it won't happen, in fact, it could possibly could, but we don't expect it, and we have no reason to assume it will occur based on anything transpired since then. We continue to believe that this application will be reviewed absent an ADCOM, and we're focused on the PDUFA date later this year. Your second question?

And with the PDUFA date coming up in November, what do you think is required to be in the product label for it to become part of the treatment guidelines?

That's a very good question. The treatment guidelines provide for both foundational treatments and others that could be add-on therapy. Maybe I'll ask Fady and Stuart to speak about what came out in the guidelines and what that could foretell for omecamtiv mecarbil being included in guidelines.

The guidelines certainly specified foundational therapy with four classes of medication, beta blockers, a RAS inhibitor, an MRA and the GLT2 inhibitor. But not all patients can tolerate all four classes, nor are all patients adequately treated. They may still have symptoms and still end up in the hospital. The guidelines also specify a number of add-on therapies, or therapies that may be supplemental to those in certain scenarios. I think omecamtiv should be one of those. The data we've generated in GALACTIC and subsequently in the analyses we’ve published indicate that sicker patients benefit even to a larger extent than mavacamten. Presumably, the guidelines would reflect that.

All right. Thank you. Thanks, Robert.

Thank you.

Your next question comes from the line of Serge Belanger of Needham & Company. Your line is open.

Good afternoon, Robert. Just a couple of questions regarding plans for a European partnership. I think you reiterated your willingness to partner omecamtiv and kind of hold onto aficamten rights. Just want to make sure that I got that right. Also, maybe just highlight for us timelines for European approval of aficamten and how you see that market opportunity relative to the U.S. opportunity.

Sure. We continue to focus on partnering omecamtiv mecarbil in Europe. It's in part because we're going to be busy with our focused omecamtiv mecarbil in the United States and our development of aficamten. We're sober to the reality of what it takes to be successful in Europe. Under Andrew's supervision, we've conducted exercises to plan how that will work, and we think it is practical. The opportunity for omecamtiv mecarbil in Europe is compelling, much like in the U.S., but it's a lesser one in light of what we imagine are some of the market access challenges and also pricing. I’ll turn it to Andrew for more on the relative opportunity.

From an opportunity point of view, the prevalence in Europe is slightly higher in terms of total number, not by much. So it's similar to the U.S., but the pricing is a good bit lower. That's what affects the overall opportunity from a European point of view. Considering the U.S. opportunity for omecamtiv and the synergies across the organization, it could become more interesting from a timing point of view. But the overall opportunity is lower, factoring in pricing.

We've been clear that one of the reasons why we're so compelled to go to market with omecamtiv in the U.S. is the concentrated customer segments around which we can build a good business here and the synergies we also intend to leverage when we market aficamten. The same holds true in Europe, but to a different magnitude. Given our need to be pragmatic, we think our focus on partnering omecamtiv mecarbil isn't to exclusively license it away but rather to seek a partner for the launch of omecamtiv mecarbil in Europe and sharing responsibilities as we go to market with aficamten.

Okay. Potential European approval of omecamtiv expected in 2023? Any timeline at this point?

We haven't spoken to that explicitly yet. It's going to be a function of when we file an MAA and seek approval, and that has not yet happened. We're focusing on the U.S. but also pursuing those interactions with EMA and in Europe. We'll give an update on that once we have something more concrete.

Okay. Let me squeeze in one more. Is it too early to talk about a potential timeline for readout of Cohort 4 in the REDWOOD trial?

Maybe just a bit. It's something we could perhaps talk about in the next earnings call. Let's see how the enrollment goes. As you know, it's an open-label of 30 to 40 patients, and I do expect this will enroll well. It might be something we can discuss on the next call.

Thanks for taking my question.

Thank you.

There are no further questions at this time. I'd like to turn the call back to speaker, Robert Blum, for closing remarks. Please go ahead.

Thank you, operator. Thanks to all the participants on our teleconference today. Thank you for your continued support and interest in Cytokinetics. This first quarter was a very, very busy and productive one. At the same time, we covered a lot of ground on this call, so I’ll just be brief in my concluding remarks. We look forward to sharing with you the open-label extension data from REDWOOD-OLE soon and also continuing to update you on our progress with both omecamtiv mecarbil and aficamten. As we move into the second half of the year, we'll carry out the first interim analysis with COURAGE-ALS. With those as key milestones for the remainder of the year, we thank you for your attention today. And with that, we can conclude the call.

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