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Cytokinetics Inc
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Good afternoon and welcome ladies and gentlemen to Cytokinetics' Fourth Quarter 2022 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 question-and-answer after the presentation. [Operator Instructions]
I will now turn the call over to Diane Weiser, Cytokinetics' Senior Vice President of Corporate Communications and Investor Relations. Please go ahead.
Good afternoon and thanks for joining us on the call today. Robert Blum, President and Chief Executive Officer who will begin with an overview of the quarter and recent developments. Fady Malik, EVP of R&D will provide updates related to omecamtiv mecarbil and aficamten, as well as other drug candidates comprising our early clinical development pipeline. Andrew Callos, EVP and Chief Commercial Officer will speak further about omecamtiv mecarbil and our specialty cardiology 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 of the past quarter and Ching Jaw, SVP and Chief Financial Officer will discuss our 2023 financial guidance and corporate development strategies. Finally, Robert Blum will provide closing comments and review expected key milestones for 2023.
Please note that portions of the following discussion including our responses to questions contain statements that relate to future events and performance rather than historical facts and constitute forward-looking statements. Our actual results might differ materially from those projected in these forward-looking statements.
Additional information concerning factors that could cause our actual results to differ materially from those in these forward-looking statements is contained in our SEC filings including our current report regarding our fourth quarter 2022 financial results filed on Form 8-K and our Form 10-K each of which were filed today. We undertake no obligation to update any forward-looking statements after this call.
And now, I will turn the call over to Robert.
Thank you, Diane and thanks to all for joining us on the call today. The fourth quarter of 2022 was productive across our pipeline with continued progress being made through the beginning of this year.
Beginning with omecamtiv mecarbil, yesterday, we received a complete response letter from the FDA. The letter communicated that GALACTIC-HF is not sufficiently persuasive to establish substantial evidence of effectiveness for reducing the risk of heart failure events and cardiovascular death in adults with chronic heart failure with HFrEF in lieu of evidence from at least two adequate and well-controlled clinical investigations.
FDA stated that results from an additional clinical trial of omecamtiv mecarbil are required to establish substantial evidence of effect for the treatment of HFrEF with benefits that outweigh the risks.
As we stated in our call this morning, we expect to request a meeting with FDA in order to understand FDA's views regarding the CRL and what may be required to support potential approval of omecamtiv mecarbil in the United States.
However, as mentioned this morning, we have no plans to conduct an additional clinical trial of omecamtiv mecarbil and our focus remains on the development program for aficamten.
While disappointing, this is a scenario for which we prepared. As Andrew will elaborate, in anticipation of this potential outcome, a substantial portion of our anticipated 2023 commercial spending and hiring was gated on the potential approval of omecamtiv mecarbil. Our commercial infrastructure has also been designed and developed with the ability to pivot to focus on aficamten in line with our specialty cardiovascular franchise strategy.
Moreover and in parallel as you'll be hearing more from my colleagues, we will continue in 2023 to press forward with regulatory authorities to seek approvals for omecamtiv mecarbil in other countries and as may provide support to corporate development and business development activities.
As mentioned previously, we believe in the science underlying omecamtiv mecarbil and the demonstrated clinical evidence to potentially benefit patients with advanced and worsening heart failure. With that said however, we will not bet the company on omecamtiv mecarbil and ours is a broad pipeline on novel muscle biology-directed drug candidates.
Cytokinetics is well-positioned to press forward with aficamten as represents our next major opportunity to bring forward an important new medicine to serve patients in need. And to that end in the fourth quarter, the development program for aficamten progressed in both obstructive and non-obstructive HCM. As Fady will explain, we're poised for an important year with data expected from Cohort 4 of REDWOOD-HCM in NHCM this coming weekend at the ACC scientific sessions in New Orleans and results from the pivotal Phase 3 trial SEQUOIA-HCM later this year in Q4.
Concurrently, we have plans to substantially expand the development program for aficamten by beginning two new Phase 3 clinical trials in 2023; one, in OHCM with aficamten as monotherapy and one in NHCM.
As Stuart will elaborate for reldesemtiv patient enrollment continue to encourage ALS following the first interim analysis that occurred last quarter and we expect the data monitoring committee to conduct the second interim analysis for the ongoing trial in the second quarter of this year. We believe reldesemtiv can represent an entirely new pharmacology for ALS patients underserved by the lack of a muscle-directed therapy.
Entering 2023, Cytokinetics remains on strong financial footing with over two years of forward cash owing to our strategic and gated build of our commercial capabilities as well as our creative deal-making and prudent investment spending. We expect our burn rate in 2023 to be within a comparable range to 2022 despite our broadening of the clinical development program for aficamten as well as our expanding and extending our early clinical development pipeline as you'll also hear more during our call today.
And despite the setback for omecamtiv mecarbil, our mission remains the same as it has been for 25 years now to bring forward new medicines for patients with diseases of impaired muscle function and our convictions run as strong as ever.
With that I'll turn the call over to Fady.
Thanks, Robert. Before we move on to aficamten, I want to express my disappointment in this outcome for omecamtiv mecarbil and also share my gratitude to the many employees investigators and patients who contributed to the development program over the years.
While we continue to work with FDA and assess the next steps for omecamtiv mecarbil. In the fourth quarter, the European Medicines Agency accepted the marketing application for omecamtiv mecarbil. JIXING announced that the Center for Drug Evaluation of the National Medical Products Administration of People's Republic of China accepted the NDA submission for omecamtiv mecarbil.
We'll continue to pursue international approvals for omecamtiv mecarbil as we assess its future for the program in the US.
Moving on to aficamten. We made excellent progress in the fourth quarter with nearly 100 clinical trial sites opening to screening, enrollment increased substantially in SEQUOIA-HCM in the fourth quarter and into early 2023. We've now enrolled more than two-thirds of the targeted 270 patients and believe we're on track to complete enrollment in the second quarter with results expected in the fourth quarter of the year.
During the quarter, we also completed enrollment in Cohort 4 of REDWOOD-HCM. We plan to share data from this cohort in non-obstructive HCM patients in a poster session at the American College of Cardiology Scientific Sessions this coming weekend, setting us up for advancement into a pivotal Phase 3 clinical trial in patients with non-obstructive NHCM in the second half of the year.
Related to REDWOOD-HCM, during the quarter we were also pleased to announce the full results from Cohorts 1 and 2 of REDWOOD-HCM were published in JACC elaborating on its next-in-class profile. In addition, we further preparations for our second Phase 3 clinical trial of aficamten, as monotherapy compared to metoprolol in patients with obstructive HCM. We're calling the trial MAPLE-HCM, which stands for metoprolol versus aficamten in patients with left ventricular outflow tract obstruction and exercise capacity.
The trial is expected to begin within the second quarter of this year. But in advance I'd like to share a few key points about this design. MAPLE-HCM is a Phase 3 multicenter randomized double-blind active comparator trial in patients with symptomatic OHCM and elevated LVOT gradient. It is expected to enroll approximately 170 patients.
The primary endpoint is change in peak VO2 assessed by CPET from baseline to week 24. Secondary endpoints include change in NYHA class, KCCQ NT-proBNP and measures of structural remodeling. We look forward to sharing more details about the trial upon the opening of enrollment.
Looking to our earlier-stage pipeline, during the fourth quarter we began a Phase 1 study of CK-136, our cardiac troponin activator in development for the potential treatment of patients with HFrEF and other types of heart failure, such as right ventricular failure resulting from impaired cardiac contractility. The advancement of CK-136 extends our cardiovascular franchise as it may provide differentiated effects for the potential treatment of these other forms of heart failure by employing an alternative mechanism of action within the sarcomere. We expect to share data from the Phase 1 trial in the second half of the year.
Additionally, more recently, we presented preclinical data related to a newer compound CK-4021586 or CK-586. It's another cardiac myosin inhibitor. CK-586 has a mechanism of action that's distinct from aficamten and its advancement affords us the potential to explore the therapeutic application of cardiac myosin inhibition to treat certain types of heart failure with preserved ejection fraction where hypercontractility may play a role. We look forward to advancing this compound into clinical development during this first half of the year.
Despite the CRL for omecamtiv mecarbil, we have three other cardiovascular drug candidates advancing in development, led by Aficamten in the pivotal Phase 3 clinical trial SEQUOIA-HCM. Our cardiovascular franchise emerging from our Sarcomere Directed research, continues to deliver on the promise of new potential medicines for patients.
With that, I will turn the call over to Andrew, to speak about Omecamtiv Mecarbil and our specialty cardiology franchise strategy.
Thanks, Fady. While we're disappointed by the complete response letter we received yesterday, this was a scenario for which we had planned and budgeted. As we've discussed, a substantial portion of our anticipated 2023 commercial spending and hiring was gated on the approval of omecamtiv mecarbil.
As a result of our receiving CRL, we will dial back on what would have been our commercial spending had FDA approved on omecamtiv mecarbil. With that said, the commercial readiness infrastructure that we have established was always developed with an eye toward a cardiovascular franchise strategy and the future launch of aficamten and additional cardiac muscle modulators.
Over 90% of our commercial team has responsibilities that are not solely dedicated to omecamtiv mecarbil. Our care team is predominantly the same team needed to support aficamten. So, we have no plan for reductions in our workforce. We will also not be expanding our commercial organization in 2023, but instead, shifting our focus on now preparing for the potential approval and launch of aficamten.
This is not the path we had hoped for, for our company and for patients with heart failure with reduced ejection fraction, but we are nimble and will pivot and now execute on this planned scenario. In Q4, we continued commercial activities related to aficamten. Last quarter we completed an initial go-to-market strategy for aficamten, and progressed, our commercial readiness plans.
We are within the window, in which much work needs to be done to prepare for potential global launches of aficamten, across potentially multiple indications. Cardiac myosin inhibition is proving to be important for the treatment of patients with OHCM, and we expect that will propel Cytokinetics to be a global specialty cardiovascular company, leading with aficamten and necessitating our important planning and executing in both 2023 and in 2024.
With that, I will turn the call over to Stuart to provide an update on reldesemtiv.
Thanks Andrew. On the neuromuscular side, reldesemtiv remains a key late-stage program for our company. In the fourth quarter we proceeded with patient enrollment in COURAGE-ALS with now over 450 patients, enrolled to-date or more than three quarters of our target patient enrollment. We're on track to complete enrollment in the second quarter of 2023 and readout results in 2024.
During the quarter we announced the continuation of COURAGE-ALS, following the first interim analysis for futility conducted by the Data Monitoring Committee which reviewed unblinded data from the trial. We expect the second interim analysis to take place in the second quarter, which will also assess for futility as well as the option for a potential fixed increase in total sample size to augment the statistical power of the trial.
Also during the fourth quarter of 2022, we continued to enroll patients who completed COURAGE-ALS into COURAGE-ALS OLE or the Open Label Extension and we advanced plans for a managed access program for reldesemtiv to be available to patients who have completed any of our previous ALS trials, including VITALITY-ALS the Phase 3 clinical trial of tirasemtiv and FORTITUDE-ALS Phase 2 clinical trial of reldesemtiv.
Finally late last year, we were pleased to present data at the 33rd International Symposium on ALS MND from an analysis of FORTITUDE-ALS showing that patients predicted survival risk score was strongly correlated with decline in ALSFRS-R and suggesting that the inclusion criteria selected for COURAGE-ALS will have the intended outcome of enriching for participants, with more rapidly progressing disease, while minimizing, but not excluding participants with more slowly progressing disease.
And with that, I will turn it over to Robert Wang.
Thanks, Stuart. We ended the fourth quarter with approximately $830 million in cash and investment's. Our revenue in Q4 2022 came primarily from Astellas to co-fund COURAGE-ALS. Our fourth quarter 2022 R&D expenses increased to $75 million from $43.5 million in the fourth quarter of 2021, primarily due to increases in spending for clinical development activities for SEQUOIA-HCM and COURAGE-ALS and for our other cardiac muscle inhibitor and early research programs.
Our fourth quarter 2022 G&A expenses were $54 million up from $33.8 million in Q4 2021, due primarily to higher outside service spending in anticipation of the potential commercial launch of omecamtiv mecarbil, and our increase in personnel-related costs including stock-based compensation. And now Ching will review our financial outlook 2023 guidance and corporate development strategies.
Thanks, Robert. Today, we announced our financial guidance for 2023. The company anticipates revenue will be approximately $5 million driven by dollar reimbursement of the cost of COURAGE-ALS. In addition, we expect to receive $50 million in a milestone payment from Royalty Pharma upon the start of the pivotal Phase 3 clinical trial of aficamten in non-obstructive HCM.
Operating expenses will be in the range of $420 million to $450 million and net cash utilization will be approximately $350 million to $375 million. Our current cash balance of approximately $830 million represents more than two years of forward cash based on our projected 2023 operating expenses and net cash utilization.
With our having received a CRL from the FDA we will not incur a substantial portion of cost for what would have been our planned spending to launch omecamtiv mecarbil in the United States, a majority of which was purposefully gated on potential FDA approval.
As Andrew mentioned earlier, related to omecamtiv mecarbil we planned for the possibility of this scenario and have managed our spending judiciously by gating majority of this potential commercial spending to FDA approval. As a result a significant majority of our commercial infrastructure can be redeployed to support potential global launch planning for aficamten.
Looking to other programs and spending this year, of our anticipated $150 million in clinical development spending in 2023 roughly 60% will be allocated to development program of aficamten.
As we have done in the past, we aim to end 2023 with more than two years of cash runway. We remain in a strong cash position, but as a testament to our goal of maintaining multiple levers for accessing capital, we are continuing to pursue additional business development and corporate development deals this year.
And with that, I'll turn the call back over to Robert Blum.
Thank you, Ching. While things didn't go the way we had hoped for omecamtiv mecarbil with our having received a CRL from FDA, 2022 was still a year of very meaningful progress with our company maturing and transforming. We are familiar with overcoming challenges at Cytokinetics. And as Andrew said, we planned for this scenario and we are prepared to maintain our momentum without pause.
As we assess potential next steps for omecamtiv mecarbil in the United States, in 2023 our priority remains focused to aficamten which is advancing in a broadening development program with several important near-term milestones this year. We look forward to presenting important new data arising from REDWOOD-HCM in both non-obstructive and obstructive HCM this weekend at ACC and beginning two more Phase 3 clinical trials as part of the development program for aficamten. And in addition, we look forward to results from SEQUOIA-HCM later this year.
In recent years, we have been looking to this next-in-class cardiac myosin inhibitor, as the principal fulcrum on which we build our commercial business in the United States and internationally and that has not changed with the recent FDA action. Reldesemtiv also represents a promising late-stage opportunity and we also have plans in the coming year to expand and advance our early-stage pipeline to support our continued corporate development. Our future remains bright and as always, we appreciate the support of our shareholders.
Now, I'll recap our upcoming milestones for 2023. For omecamtiv mecarbil, we expect to request a meeting with FDA to understand what may be required to support potential approval of omecamtiv mecarbil in the United States. And we expect to engage with EMA regarding the MAA for the treatment of HFrEF. For aficamten, we expect to present data from Cohort 4 of REDWOOD-HCM and data from 48 weeks of treatment with aficamten in FOREST-HCM at the American College of Cardiology 72nd Annual Scientific Sessions this weekend. And we expect to complete patient enrollment in SEQUOIA-HCM in Q2 2023 with results expected from that trial in Q4 2023.
We expect to begin MAPLE-HCM the second Phase 3 clinical trial of aficamten as monotherapy in patients with obstructive HCM in Q2 2023 and we expect to begin a Phase 3 clinical trial of aficamten in non-obstructive HCM in the second half of 2023. And also, we expect to advance our US go-to-market strategy for aficamten during 2023. For CK-136, we expect data from the Phase 1 study of CK-136 in the second half of 2023.
For reldesemtiv, we expect the Data Monitoring Committee to conduct the second interim analysis from COURAGE-ALS in Q2 2023. We expect to complete patient enrollment in COURAGE-ALS also in Q2 2023 with results expected in 2024. And for our preclinical development and ongoing research, we expect to advance CK-586 into clinical development in the first half of this year.
And operator, with that, we can now open up the call, please, to questions.
[Operator Instructions] And our first question is from Yasmeen Rahimi with Piper Sandler. Your line is open.
Good afternoon.
Good afternoon, Robert. And I'm deeply sorry for the outcome of omecamtiv. I guess, my one question is directed to Fady in regards to SEQUOIA. Is there -- do you guys get notified if patients have any sort of ejection fraction drops or any safety signals that arise? And if you could comment on what you guys are seeing on the blinded basis? And then, I'll jump back into the queue in respect your wishes of one question per person.
Thank you, Yasmin, for that. I can't really comment on emerging safety data. We -- I will tell you what we see, which is that we don't see ejection fractions that are dealt with by merely dose reduction. Those are taken care of by the IWRS system that dispenses drug. And in order to dispense drug that sites have to enter in the site red ejection fraction. That's done by a cardiologist that's not part of the study team and is blinded to study treatment.
But the -- so we don't get notified if EF drops below 50%. If somebody's ejection fraction dropped below 40% that would require a termination of treatment and that would become a noted event, which we would become privy to. But I'm -- we're pleased with how things are going and maybe I should just put it that way.
Thank you so much, Fady, for the color. Greatly appreciated and I’ll jump back into the queue.
Thank you, Yasmeen.
Thank you.
Thank you. One moment for our next question. And our next question is from Joe Pantginis with H.C. Wainwright. Your line is open.
Hi, Joe.
Hey, guys. Good afternoon. Thanks for taking the question. So curious, so Robert this morning you talked about how it's early to discuss in the iterative process with regard to omecamtiv in Japan and the EU potential there. I was just curious if you had any commentary about the approach that Ji Xing is taking and if there's any differentiation?
Yes. So, I should allow Ji Xing to comment there in the driver's seat as it relates to the regulatory submission in China. But, I think, we've learned from the interactions with FDA as to how we might best position omecamtiv mecarbil in other jurisdictions.
And I would not consider that what happened with FDA to necessarily close the door on any other countries, especially in light of the fact that we've taken different tact. Maybe that's the best way I could say it. Outside the United States our strategies are different.
Appreciate the comment.
Thank you.
Thank you. One moment for our next question. And our next question is from Jason Zemansky with Bank of America. Your line is open.
Good afternoon. Thank you so much for taking our questions. Curious, as you think about a go-to-market strategy for aficamten. Any sense on how one could potentially operationalize the dosing monitoring whether it's a focused echocardiogram, or potentially either four weeks or eight weeks something to avoid kind of the two-week potential monitoring, that we see within the SEQUOIA Phase 3 design? Thanks.
So, as you probably can well appreciate the way in which this drug may ultimately be labeled, will be informed by how it was studied in clinical research, but I'll ask Fady to elaborate.
Yes. I mean, I think first of all the echos can be done in a quite focused fashion. The only things you need to assess are the gradient and the ejection fraction. We do lots of other views and things like that, in echocardiograms that can take longer. But it's really up for the -- up to the site, to decide on how to implement that. With regards to your question about dosing, I should be clear that the every two-week schedule, we employed in SEQUOIA represents a minimum dosing interval.
There's no penalty. There's no reason, why you couldn't employ a longer dosing interval, if that was the patient's preference or the physician's preference. What I would expect the label to reflect is that, you wait at least two weeks before making a dosing change and it's up to the patient and the physician, as to how long they want to wait after that.
I think one of the things that we are optimistic about is that SEQUOIA, will be enabling of patients to get to target dose rapidly, and enabling a symptom relief rapidly. And I think that's ultimately going to play to our strategy, which would be speaking to how the category may ultimately expand, in light of potential availability of aficamten and I think Fady, may have another comment to make.
A follow-up. I mean, I think these patients obviously, have lived with their symptoms for a long time. I don't think that necessarily detracts from how soon, they would like to see relief from their symptoms. If you had a choice between spending weeks or months to get to feeling relief from something you have carried with you for many years, versus a shorter period of time, I'm not sure, why patients wouldn't select a shorter period of time even as they maybe have been living with their disease for a long time. So, we think the more rapid titration that we've employed in SEQUOIA, in terms of, the dosing interval will be something that would be attractive to patients.
Interesting. Thanks so much for the color
Thank you.
Thank you. One moment for our next question. And our next question is from Srikripa Devarakonda with Truist Securities. Your line is open.
Hi, this is Ishan. I'm on for Kripa. So with omecamtiv, you have said that you don't want to run another trial in US. So just wondering, what is the likelihood of you either divesting this asset to a company that already has a franchise in place, or has the capital? And what is the threshold for you to want to do this? Thank you.
Yes. So a number of you have been posing that question. And we're just within 24 hours of having received a disappointing CRL and how we might ultimately monetize omecamtiv mecarbil is not something for which we're yet ready to communicate publicly. What I will say is divesting omecamtiv mecarbil to be permitting of another company to run clinical trials would be something that we should consider. But I think we've got experience with other companies running clinical research for omecamtiv mecarbil and I don't think that is something that we have high confidence is in the interest of science or patients.
So what we may do instead is around partnering omecamtiv mecarbil. And I think that's where we've been leaning already. Already we've been well engaged with other companies who have appetite to partner around omecamtiv mecarbil. And that's something that I think is more likely going to be something that moves the needle for Cytokinetics.
Thank you.
Thank you.
Thank you. One moment for our next question. And our next question is from Carter Gould with Barclays. Your line is open.
Hi. Good afternoon guys. Thanks for taking the question. Looking forward to seeing you down in New Orleans this weekend. I guess that's a good segue to our question, which is in the past you've talked about the non-obstructive data being sort of a pilot for moving into HFrEF. And I guess how do you think now about the appropriate jumping off point for doing a study in HFpEF with one of the myosin activators and I guess really how does 586 movement into the clinic I guess either complicate or complement that strategy? Thank you.
Yes. So I'll start and turn it over to Fady. But our movement of 586 into the clinic underscores our enthusiasm for myosin inhibition in patients with HFpEF who have hypercontractile ventricles. What you're seeing in NHCM, I should say what we're seeing in NHCM and you'll see on Sunday we believe augurs well for this mechanism in certain patients with HFrEF as will be now able to be explored with 586 as it moves forward. So I'll turn it over to Fady to speak to what in particular we see in NHCM as reads on those patients with HFpEF.
We laid this strategy out in 2018 at an R&D Day which is that OHCM represents the vanguard of application for a cardiac myosin inhibitor with obvious extension to NHCM but then NHCM provides a genetic model if you will of a more severe form of heart failure preserved ejection fraction. That is in the patients in whom that disease manifests as high ejection fraction thickened ventricles in many ways frankly you have difficulty distinguishing them from NHCM patients in absence of doing the genetics.
And so we think of this as a natural progression of the development program and the entry of 586 into the clinic enables us to potentially use a different molecule in heart failure with preserved ejection fraction as maybe less complicated in terms of making it available in that population in the long-term.
But you also asked about properties of 586, and while we can't be so specific yet we do believe that 586 operates by a different mechanism than does aficamten and more of that and why and how that may afford a potential advantage and how path will come over time.
Thanks, guys.
Thanks, Carter.
Thank you. One moment for our next question. And our next question is from Tessa Romero with JPMorgan. Your line is open.
Good afternoon, Robert and team. Thanks so much for taking our question. So, one commercial question for me. Can you talk a little bit about your market intel and what are the attributes about aficamten's emerging profile that may be the most kind of needle moving for the physicians in the clinic here? And what are the prescribing factors that are most important for physicians? And how much variability is there in the marketplace on that? Just kind of curious, if you're hearing that there could be some differences among various segments of the marketplace of HCPs. Thanks, so much.
Sure. So I'm going to ask Andrew to comment and I'll just start by saying that, you won't hear us saying anything comparative aficamten versus mavacamten. We think BMS is doing a good job with mavacamten and setting the table nicely for that compound doing well in a select number of patients with oHCM, but we are doing market research around aficamten and where its profile may be enabling of an expansion of the category. And I'll ask Andrew to elaborate on that.
Sure. Thanks, Robert and thanks for the question. Probably the key differences that we're hoping or at least in terms of differentiation, really comes down to healthcare utilization, as well as the physician and patient experience, both starting and staying on aficamten should it get approved. So things like not having to worry about other products that a patient could take around drug-to-drug interactions or fetal toxicity for say a female of child-bearing years, the amount of echos that could be required, the type of REMS programs. So, these are real or could be real challenges and differences, should one product have and require less utilization and resources from healthcare and less monitoring and kind of patient follow-up. So I think they are coming to be real issues in the marketplace potentially or differences I should say, not issues. But obviously, we have to wait until Phase III and what our data would bear out to see, if we can truly differentiate.
Having a second cardiac myosin inhibitor in a category not unlike we've seen in other therapeutic categories like pulmonary arterial hypertension for instance is enabling of an expansion to patients who might not otherwise be receiving the first-in-class compound. And we've designed aficamten very much to be enabling of a broad therapeutic window, faster onset, faster reversibility, were that to be required. And as such that could be supportive of the use of aficamten, not just in certain HCM centers of excellence and certain patients, but rather in other patients who might stand to benefit as well and as would be prescribed by other cardiologists too. So our goal is ultimately to afford physicians and patients a choice with regard to a myosin inhibitor for their patients.
Thank you for taking our question.
Thank you.
Thank you. One moment for our next question. Our next question is from Dane Leone with Raymond James. Your line is open.
Hi Dane.
Hi. Thanks for taking the questions and congrats on the progress standing to 2023 now. Just maybe a few for me that have been topical for a lot of investors recently. Maybe if you could opine in terms of your discussions with the cardiovascular team over at the FDA and how explicit they have been in terms of endpoints for pivotal nonobstructive hypertrophic cardiomyopathy studies? Your peer it's obvious is using a KCCQ endpoint change from baseline event peak VO2, which has some similarities from the pivotal studies that have been done in obstructive.
But I'd be interested in your thoughts of, kind of, one, what the hurdle is for a clinically meaningful change that the FDA team would review? And then secondly, if your experience leads you down the same pathway of how to design that pivotal study? And then a real quick one after that. The enrollment for SEQUOIA is still ongoing. I think some people are asking right now how close do you -- does your team think you're going to cut it in terms of having that top line data before year-end? Thank you.
So I'll answer the second part of your question and then ask Fady to answer the first part. We're pretty confident that we're moving towards completion of enrollment in SEQUOIA to be confident that we'll see data in Q4. If you're asking if that's October versus November versus December, I think that we probably can't give you the resolution on that that you're interested in recognizing that the study is not yet concluded in enrollment. And some of those are things that relate to once it is concluded, how long might we need for database lock and what kind of outstanding queries might we still expect. We're obviously cleaning data as it's coming in. But I think we can confidently say Q4, I'm not sure I'm going to do any better than that right now.
Regarding endpoints in a pivotal Phase 3 study of NHCM, I think when we elaborate on that study once it is underway, you'll see some similarities to the ongoing Phase 3 study with mavacamten but also some notable distinctions based on aficamten has a different profile.
But I'll ask Fady to comment on what's clinically meaningful with regard to some of these end points.
Well, I think the endpoints we can use in NHCM in a lot of ways mirror what we'll use in OHCM. They're function and their symptoms. They include peak VO2. They include KCCQ, they include NYHA class, and then secondarily think biomarkers and things that we've measured before.
So conceptually there's not I think a tremendous difference between the two. I think in part the question might be what might you order first? And what might you focus on? And I think any of them are meaningful -- potentially meaningful and potentially approvable. KCCQ has been used to -- as an approvable endpoint in pivotal trials before. And obviously we see the BMS design incorporates that into their primary endpoint and PCO2 is what we're using in SEQUOIA.
You know, it's a magnitude in general people are looking for magnitudes that are up five points or more in the KCCQ that's a little arbitrary. I think, you have to look at the whole distribution and ask is that driven -- if you were less than five, but you had a substantial number of patients that had very large improvements that's pretty meaningful for those patients.
And if others don't respond as a treatment that is being given to improve patient symptoms they can tell you whether they're feeling better and whether the treatment should be continued in them. So we'll have those discussions with FDA. Ultimately, the results will inform how we approach potential discussions with FDA around expansion of a label for -- in NHCM.
My hope is that you'll see data in the poster on Sunday that will be revealing as to how aficamten may be received in NHCM. And again, I'll remind you we're going to have a call with investors and analysts Monday morning to walk through those data as they were presented the day before. And that will inform how we might can -- elaborate on what would be a Phase 3 study design in connection with duration of treatment and time to end points.
Excellent. Thank you so much.
Thank you.
Thank you. One moment for our next question. And our next question is from Jason Butler with JMP Securities. Your line is open.
Hey, Jason.
Hi, Robert. Thanks for taking the question. Just one on the upcoming reldesemtiv interim. Can you give us any more details in terms of the number of patients that you can add? Is it just one option, or are there multiple options of adding different amounts of patients? And then any color on how long adding additional patients would add to the enrollment time lines? Thanks.
Yes. I'm going to ask Stuart our Chief Medical Officer to comment, but I'll mention that we haven't disclosed what is the specific number of patients that could be added. It's a single number but maybe he can speak to how we're going to approach that.
Thank you, Jason. It's a good question. By design it's actually a fixed number of patients that would be upsized depending on the conditional power that's observed by the Data Monitoring Committee. And then essentially designing that way to mask sort of a magnitude of change in ALSFRS-R. So the -- essentially it's binary either upsizing or not.
With respect to time frame for continuing enrollment, I think that's sort of better discussed when -- if the best recommendation comes forward from the Data Monitoring Committee. But enrollment is going very well in COURAGE-ALS and we don't expect a major delay in completing enrollment given of this trial's upside.
Maybe just to expand on that a little bit. I'll ask Fady to comment on how the Data Monitoring Committee is being guided.
Yes. So, I think the interim analysis uses what's called a promising zone construct, which is either -- if you have a -- it's a construct trying to avoid with like term the near-miss scenario. You've assumed a treatment effect you power a study based on that assumption. The trial progresses and the treatment effect may be larger than you assume which should certainly be a good scenario to be in. It could be a little less than you assumed.
And if it's small enough even it may be positive and clinically meaningful you may no longer have the power to be confident you would end up with a positive study. So, this is a one-time adjustment that the Data Monitoring Committee can make to a fixed size, fixed increment that would increase the power of the study.
And the other scenario is there is a chance the study could stop for futility as well if it looked like you really had no power at all to see a treatment benefit. So, that's how I would describe the interim analysis in high-level terms.
Most of those are possible, outcomes they may not be probable, but we thought it was important to lay them out there. There is an adaptive element if you will to the design and conduct of COURAGE-ALS as we think it is our responsibility for this potentially being a first muscle-directed therapy in ALS.
So, we'll know soon enough what path we're going down. And more likely than not we expect that the study will conclude enrollment without it either stopping early or being upsized in Q2.
Thank you.
Thank you.
Thank you. And our next question comes from Charles Duncan with Cantor Fitzgerald. Your line is open.
Hi Charles.
Hi, good afternoon Robert. Thanks for taking the question. I too want to go off script off the AFI script and ask a follow-up question on relde and I apologize upfront, it's probably a three-part question. That is first of all with regard to that fixed increase in sample size could you provide more color? Is it call it a 10% or 25%?
Secondly, with regard to the ongoing OLE, do you have a sense of the rollover and persistence and has Relyvrio impacted that? And third again going to Relyvrio, is that in some ways changing or impacting the types of patients that are wanting to enroll in COURAGE-ALS?
I'm going to be turning to Stuart to answer these questions and anything Fady wants to add on top of that. We're not commenting on the number the patients that might be added. But to your question is it 10% more 25% more, let me just say that it's not so many more that we don't expect that the study could still conclude enrollment this year and therefore we'd still expect results next year if that helps you. It puts it into a ZIP code. Then I'll turn to Stuart maybe to answer the other two questions.
Hi, Charles. Thank you for your questions. With respect to the open-label extension, I think it's -- we can say that most of the patients are rolling over into the extension. So that study is going well. The impact of Relyvrio [ph], not surprisingly there has had some impact in terms of enrollment in North America. But, we have a large portion of patients enrolling in Europe as well as Australia.
So, it really hasn't had a meaningful impact in terms of enrollment in the study. Furthermore, because this is now an approved therapy in North America, we are allowing patients even if they are treated with Relyvrio to enroll in the trial. So any approved therapy is permitted as background therapy in COURAGE-ALS.
That's interesting. And then the last one in terms of enrollment that is being allowed. Is that what you just had?
That's right. They're allowed to enroll in the study if they're on Relyvrio. That's by incorporated by amendment. It is similar to we allow patients on [indiscernible] or patients on [indiscernible] too participate.
Yes. Got it. Thanks for taking the questions.
Yes. Thank you.
Thank you. One moment for our next question. And our next question is from Justin Kim with Oppenheimer. Your line is open.
Hi, Robert and team. Thanks for taking the additional question. So I think this morning covered a lot of ground across the pipeline, but just maybe a clarification in terms of the second MAPLE study for aficamten in oHCM. Just wondering what type of blocking and tackling remains before initiating the study and if it's reasonable to expect the initiation after completion of enrollment for SEQUOIA?
Yes, I can comment on that. Thanks for the question. It's a complicated study to start from the point of view of drug supply and things as we've said before. We are packaging and labeling and manufacturing four different supplies an aficamten a placebo for aficamten, metoprolol and metoprolol for aficamten or a placebo for metoprolol. So, supply for this study is a bit more complicated than some of the other studies we've done. So that's one of the pieces of blocking and tackling we're taking care of.
In the meantime we are embarking on startup activities at sites that include IRB submissions and contracts and negotiations all those sorts of things. And as you mentioned, SEQUOIA is ongoing in terms of its enrollment and our preference obviously is not to compete against ourselves. So, there's a bit of load management here that's ongoing. And I think we'll see the study start in the same time frame that we see SEQUOIA winding down in terms of enrollment.
Okay. Great. Thanks, and look forward to transition this weekend.
Thank you.
Thank you. One moment for our next question. And our next question is from Salim Syed with Mizuho. Your line is open.
Hey, Salim.
Hey, guys. Thanks for the question. I guess one for me on SEQUOIA. As folks start to pivot on handicapping this trial, does Cytokinetics have any data at all on peak VO2 change for aficamten, even if from the OLE or is the powering here of 1.5 on peak VO2 changes based on what EXPLORER did and mind you that was at 1.4 and that the notion aficamten is just a better product. And just quickly related to that, will you actually give us the baseline peak VO2 prior to readout, so we can handicap the trial?
Good questions. I'm going to ask Fady to answer them.
So Salim, I think you know probably that we haven't reported it in the protocols for REDWOOD and FOREST don't include exercise testing, peak VO2 testing. So we don't have any data per se with that test in aficamten. 1.5 versus 1.4, I think that's just a matter we picked a round number and the powering was calculated in a way that gives us over 90% power to achieve that metric.
So in terms of sheer number of patients enrolled where SEQUOIA is somewhat larger than EXPLORER was. The p-value for the peak VO2 at 1.4 was less than 0.01. And so we should be quite well powered to see an improvement of 1.5, 1.4 even down to 1.0, which would represent I think in some ways what people think of as clinically meaningful with regards to peak VO2. So that's really what I can say about it now. I think we have a nice proof-of-concept in terms of how that endpoint can be impacted by a cardiac myosin inhibitor. And so that helps derisk if you will the primary endpoint of this trial.
Thanks, Fady. Will you provide the baseline at some point you think or...
Probably right before you see the primary outcome. But no I don't think we'll be providing the baseline characteristics prior to the study's presentation.
Okay. Got it. Thank you so much.
Thank you.
Thank you. One moment for our next question. And our next question is from Serge Belanger with Needham Co. Your line is open.
Hey, Serge.
Hey, Robert. Good to hear you going this afternoon. Two questions on the aficamten Phase 3 program. First one on enrollment. So it looks like it's going to take about 14 to 15 months to enroll the 270 patients in the SEQUOIA trial. Just curious if you expect a similar pace of enrollment for the MAPLE study as well as the other Phase 3 trial in HCM, given that you can have three Phase 3 trials running concurrently? And then secondly, in terms of the regulatory strategy, should we expect that both the MAPLE and the HCM Phase 3 trial to support separate sNDAs once they're complete? Thanks.
Yes. So I'll answer the second part first. Our registration strategy the critical path is paved with SEQUOIA-HCM and we'll be submitting based on that in oHCM before MAPLE concludes. But you could imagine MAPLE would be the subject matter of a supplemental NDA following potential approval. And similarly the Phase 3 study in nHCM, yes to your question again would represent a separate submission as could be supportive of an expanded label in nHCM. So all three of those being separate from a regulatory standpoint.
What I should also mention is that our capabilities are such now that we would anticipate unlike with omecamtiv mecarbil where there is a significant time lag from a US submission to a European 1 in HCM we're now equipped we think to be submitting more in parallel globally in order to be able to lend support for potential approval as would come internationally in more rapid succession. So I'll turn now to Fady to address your first question regarding expected duration of enrollment in those second and third Phase 3 studies.
Yeah. I think it's a question more related to the rate of enrollment which I think we will -- these trials are a little different. So with regards to nHCM, the nHCM trial doesn't really compete for the same patients that MAPLE or SEQUOIA would enroll and we likely will be winding down enrollment in SEQUOIA before these two trials really get underway in terms of enrollment. So in terms of concurrent enrollment MAPLE and nHCM, don't compete against each other. The study population in MAPLE is a bit more flexible if you will in terms of what can be enrolled. And so it may help I would say continued enrollment at the pace that we've seen in SEQUOIA. And I think it's a little too early. I mean we've -- we enrolled the nHCM cohort in REDWOOD quite briskly and I'm optimistic we can do so in a Phase 3 trial as well. Hopefully, that answers your question.
Yeah. Thank you.
Thank you.
Thank you. One moment for our next question. And our next question is from Madhu Kumar with Goldman Sachs. Your line is open.
Hey, Madhu
Hey, how is it going? Thanks for taking our question. I guess kind of following up on MAPLE-HCM, I'm kind of curious, how should we think about this trial and the potential kind of clinical impact and utility of aficamten, if this trial is successful? What kind of white space in the obstructive HCM space, do you think this drug – this trial uniquely addresses? And I guess, kind of stepping back to some earlier data from last year about drug withdrawal, how do you think about that on the forward and the potential idea of monotherapy of aficamten and withdrawal of other therapies within the kind of formal clinical trial setting?
Yeah. So your question has implications both for the clinical profile but also the commercial profile. And maybe Fady can start talking about what could be the value of demonstrating effects of aficamten relative to metoprolol but then Andrew should also comment.
The MAPLE-HCM study is something our investigators and steering committee members are really excited about. They view it as a critical question to have data the support, if you will using aficamten as first-line therapy. The real question is, what benefits do you get from beta blockers as monotherapy. And in general, you do see reductions in gradient improvement in symptoms, you don't see really any improvement in exercise capacity. And so how does that compare in a head-to-head study with aficamten as may eventually support at least from a scientific perspective, its implementation as first-line therapy.
And the other thing is to look at how structural remodeling occurs in the context of beta blockade, contrasted with cardiac myosin inhibition. So well that's not necessarily an approvable endpoint. It does speak to the differences in the way the two drugs may modify the course of the disease. So I think the information is going to be very valuable to the HCM community as to how positioned this mechanism of action both in their practices but also in their guidelines.
The only thing maybe, I'll add is around from a commercial perspective that we certainly hear from patients and physicians that they would prefer to use a single product versus two products, if they could, but they don't want to do that without evidence. That evidence not only supports informed utilization, but it could also support and inform guideline adjustments, as well as the way payers think about, what steps are required prior to say aficamten getting reimbursed. Does the patient need to step through? Does the patient have to have a requirement, for multiple products? Could this remove a step for a patient. So, it's those types of areas, where a study like MAPLE could help further differentiate and inform both the prescriber and payer community.
You can well imagine payers, would look at superiority versus metoprolol, as enabling of a higher reference point for pricing. And that's something that we're mindful for too, as we think about how we might approach a go-to-market strategy for aficamten.
Great. Thanks. And we also report to seeing you this weekend [indiscernible]
Thank you.
I'm showing no further questions, at this time. I would now like to turn the conference back to Robert Blum, for closing remarks.
Thanks, everyone for joining us, not just on this call today, but also on the call this morning. I realize this call is going over an hour, so we'll be brief in these concluding remarks. So I'll just simply say, that yes, we are disappointed as it relates to the FDA action pertaining to omecamtiv mecarbil. But under every scenario, 2023 was always going to be a year about doubling down on aficamten, and committing to a higher investment spending on aficamten and an expanded development program for aficamten.
Not to say, it's not also important for reldesemtiv and our early pipeline, but I do think we're aligned with shareholder expectations that aficamten represents, an opportunity for which the return on investment should be predictably higher and we recognize that, and that's where we're going to be focused.
We're not going to be providing play-by-play with regard to, omecamtiv and all of our interactions with regulatory authorities, until such time as we have something material to talk about. And instead, you can anticipate in 2023 and starting with this weekend, we'll be talking a lot more about aficamten. With that, I'll bring this call to a close. Thanks very much, for your interest in what we're doing here at Cytokinetics, and all the support and we look forward to keeping you abreast of our progress this year.
This concludes today's conference call. Thank you for participating. You may now disconnect.