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spk12: 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 questions and answers after the presentation. We will allow for up to one question per participant. I will now turn the call over to Diane Weiser, Cytokinetics' Senior Vice President of Corporate Communications and Investor Relations. Please go ahead.
spk01: Good afternoon, and thanks for joining us on the call today. Robert Blum, President and Chief Executive Officer, will begin with an overview of the corridor and recent developments. Fadi Malek, EVP of R&D, will provide updates related to Omicampton-McCarbell and Affy-Campton, as well as other drug candidates comprising our early clinical development pipeline. Andrew Kalos, EVP and Chief Commercial Officer, will speak further about Omicamp and McCarbell and our specialty cardiology franchise strategy related to Affy Campton. Stuart Kupfer, SVP and Chief Medical Officer, will provide an update on REL Dissentive. Robert Wong, VP and Chief Accounting Officer, will provide a financial overview of the past quarter. And Ching Jha, 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 8K and our Form 10K, 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.
spk11: 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 Omicamp to McCarville 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 HF-REF in lieu of evidence from at least two adequate and well-controlled clinical investigations. FDA stated that results from an additional clinical trial of Omicantamacarbonyl are required to establish substantial evidence of effect for the treatment of HF-REF 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 omicamptamicarbo in the United States. However, as mentioned this morning, we have no plans to conduct an additional clinical trial of omicamptamicarbo, and our focus remains on the development program for aficamptam. 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 Omicampton McCarble. Our commercial infrastructure has also been designed and developed with the ability to pivot to focus on Affycampton 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 omicamptomicarbol in other countries and as may provide support to corporate development and business development activities. As mentioned previously, we believe in the science underlying omicamptomicarbol 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 Omicampton McCarvel, and ours is a broad pipeline on novel muscle biology-directed drug candidates. Cytokinetics is well positioned to press forward with Affycampton 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 Affy-Kempton progressed in both obstructive and non-obstructive HCM. As Fadi will explain, we're poised for an important year with data expected from cohort four of Redwood HCM in N-HCM this coming weekend at the ACC Scientific Sessions in New Orleans and results from the pivotal phase three trial Sequoia HCM later this year in Q4. Concurrently, we have plans to substantially expand the development program for Affy-Kempton by beginning two new Phase III clinical trials in 2023, one in OHCM with Affy-Kempton as monotherapy and one in NHCM. As Stuart will elaborate for rel-deceptive, patient enrollment continued 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 rel-deceptive can represent an entirely new pharmacology for ALS patients underserved by the lack of a muscle-directed therapy. Entering 2023, Tidal Connects 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 dealmaking 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 afi campton. 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 Omicamp to McCarble, 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 Fatty.
spk06: Thanks, Robert. Before we move on to Apicampton, I want to express my disappointment in this outcome for Omicamp to McCarble. 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 Omicamp and McCarville, in the fourth quarter, the European Medicines Agency accepted the marketing application for Omicamp and McCarville. And Xi Xing announced that the Center for Drug Evaluation of the National Medical Products Administration of the People's Republic of China accepted the NDA submission for Omicampt and McCarble. We'll continue to pursue international approvals for Omicampt and McCarble as we assess its future for the program in the U.S. Moving on to Apicampton. 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 four 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 three clinical trial in patients with non-obstructive HCM 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 one and two of Redwood HCM were published in JAK, elaborating on its next-in-class profile. In addition, we furthered preparations for our second phase three clinical trial of apicamtin as monotherapy compared to metoprolol in patients with obstructive HCM. We're calling the trial MAPLE-HCM, which stands for metoprolol versus afecamptin 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 its design. Maple HCM is a phase III multicenter randomized double-blind active comparator trial in patients with symptomatic OHCM and elevated LVOT gradients. 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 trial upon the opening of enrollment. Looking to our earlier stage pipeline, during the fourth quarter, we began a phase one study of CK136, our cardiac troponin activator in development for the potential treatment of patients with HF-REF and other types of heart failure, such as right ventricular failure resulting from impaired cardiac contractility. The advancement of CK136 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 one trial in the second half of the year. Additionally, More recently, we presented preclinical data related to a newer compound, CK4021586, or CK586. It's another cardiac myosin inhibitor. CK586 has a mechanism of action that's distinct from apicamtin, 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 Omicampton and McCarville, we have three other cardiovascular drug candidates advancing in development, led by Apicampton in the pivotal Phase III clinical trials, COIA-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 omicamptomacarbal and our specialty cardiology franchise strategy.
spk10: Thanks, Patty. 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 Omicamp to McCarble. As a result of our receiving of CRL, we will dial back on what would have been our commercial spending had FDA approved Omicamp to McCarble. 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 Afikampton and additional cardiac muscle modulators. Over 90% of our commercial team has responsibilities that are not solely dedicated to Omicampton Bacarbal. Our current team is predominantly the same team needed to support Afikampton, 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 Affecantin. 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 Affecantin. Last quarter, we completed an initial go-to-market strategy for afikantin 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 afikantin 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 afikantin and assassinating are 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 REL Deceptive.
spk02: Thanks, Andrew. On the neuromuscular side, REL Deceptive 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 enrollments. 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 REL dissentives to be available to patients who have completed any of our previous ALS trials, including Vitality ALS, the Phase III clinical trial of tirosemptive, and Fortitude ALS. Phase II clinical trial of REL dissenters. 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 ALS FRS-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 Wong.
spk17: Thanks, Stuart. We ended the fourth quarter with approximately $830 million in cash and investments. 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 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 Omicamp and McCarble, 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.
spk04: Today, we announced our financial guidance for 2023. The company anticipates revenue will be approximately $5 million, driven by a stylish 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 III clinical trial of ApiKempton in non-obstructive HCM. Operating expenses will be in the range of $420 to $450 million, and net cash utilization will be approximately $350 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 Omicantamucarbo in the United States, a majority of which was purposefully gated on potential FDA approval. As Andrew mentioned earlier, related to Omicantamucarbo, we plan 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 could be redeployed to support potential global launch planning for Affy Kempton. 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 AFI Kempton. 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 Boss.
spk11: Robert Boss. Robert Boss. Robert Boss. Robert Boss. Robert Boss. Robert Boss. Robert Boss. Robert Boss. Robert Boss. Robert Boss. Robert Boss. Robert Boss. Robert Boss. Robert Boss. As we assess potential next steps for Omicampton-McCarville in the United States, in 2023, our priority remains focused to Affy-Campton, 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 III clinical trials as part of the development program for Affy-Campden. And in addition, we look forward to results from Sequoia HCM later this year. In recent years, we've 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. REL deceptive also represents a promising late-stage opportunity, and we also have plans in the coming year to expand in 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 Omicamp to McCarville, we expect to request a meeting with FDA to understand what may be required to support potential approval of Omicamp to McCarville in the United States. and we expect to engage with EMA regarding the MAA for the treatment of HF-REF. For Affy-Campden, we expect to present data from cohort four of Redwood HCM and data from 48 weeks of treatment with Affy-Campden in Forest HCM at the American College of Cardiology's 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 III clinical trial of afikampton, as monotherapy in patients with obstructive HCM in Q2 2023. And we expect to begin a Phase III clinical trial of afecamptin in nonobstructive HCM in the second half of 2023. And also, we expect to advance our U.S. go-to-market strategy for afecamptin during 2023. For CK136, we expect data from the Phase I study of CK136 in the second half of 2023. For REL deceptive, 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 CK586 into clinical development in the first half of this year. And operator, with that, we can now open up the call, please, to questions.
spk12: As a reminder, to ask a question, please press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1-1 again. Please limit yourself to one question. Please stand by while we compile the Q&A roster. And our first question is from Yasmine Rahimi with Piper Sandler. Your line is open.
spk11: Good afternoon.
spk13: Good afternoon, Robert, and I'm deeply sorry for the outcome of Omicampus. I guess my one question is directed to Fatty in regards to Sequoia. 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 and respect your wishes of one question per person.
spk06: Thank you, Yasmeen, for that. You know, I can't really comment on emerging safety data. 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 IWS system that dispenses drugs. And in order to dispense drugs, the sites have to enter in the site-read ejection fraction. That's done by a cardiologist that's not part of the study team and is blinded to study treatment. So we don't get notified if EFs drop below 50%. If somebody's ejection fraction dropped below 40%, that would require a termination of treatment, and that would become an event to which we would become privy to. But we're pleased with how things are going, and maybe I should just put it that way.
spk13: Thank you so much, Patty, for the call. I really appreciate it. And I'll jump back into the queue.
spk11: Thank you, guys. Thank you.
spk12: Thank you. One moment for our next question. And our next question is from Joe Pangenis with HC Wainwright. Your line is open.
spk11: Hey, Joe.
spk08: Hey guys, good afternoon. Thanks for taking the question. So curious, so Robert, this morning you talked about how it's early to discuss and the iterative process with regard to Omicamptive in Japan and the EU potential there. I was just curious if you had any commentary about the approach that Ji Jing is taking and if there's any differentiation.
spk11: Yes, so I should allow Ji Jing to comment. They're 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 Omicam to McCarble in other jurisdictions. And, you know, 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.
spk08: Appreciate the comment.
spk11: Thank you.
spk12: Thank you. One moment for our next question. And our next question is from Jason Zemanski with Bank of America. Your line is open.
spk20: Good afternoon. Thank you so much for taking our questions. Curious, as you think about a go-to-market strategy for AFA Camden, Any sense on how one could potentially operationalize the dosing monitoring, whether it's a focused echocardiogram or potentially either four-week or eight-week, something to avoid, kind of the two-week potential monitoring that we see within the Sequoia Phase III design? Thanks.
spk11: Or 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 Fatty to elaborate.
spk06: Yeah, I mean, I think, first of all, the echoes can be done in a quite focused fashion. The only things you need to assess are the gradient and the ejection fraction. You do lots of other and things like that and echocardiograms that can take longer, but it's really up to the site to decide on how to implement that. With regards to your question about dosing, I should be clear that 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. You know, 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.
spk11: 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 of 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 afecamptin. And I think Fatty may have another comment to make.
spk06: 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 the shorter period of time even if 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.
spk20: Interesting. Thanks so much for the color.
spk11: Thank you.
spk12: Thank you. One moment for our next question. And our next question is from C, Rick Ripa, Deaver Conda with Truist Securities. Your line is open.
spk16: Hi, this is Nishant. Hi, everyone. This is Nishant. I'm on for Kripa. So with Omicamp, 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 a capital? and what is the threshold for you to want to do this? Thank you.
spk11: 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 Omicamp to McCarvel is not something for which we're yet ready to communicate publicly. What I will say is divesting omicamptomicarbol 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 omicamptomicarbol, and I don't think that is something that we have high confidence is in the interest of science or patients. What we may do instead is around partnering OmeCamp to McCarville, 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 OmeCamp to McCarville, and that's something that I think is more likely going to be something that moves the needle for cytokinetics. Thank you. Thank you.
spk12: Thank you. One moment for our next question. And our next question is from Carter Gold with Barclays. Your line is open.
spk07: Great. Good afternoon, guys. Thanks for taking the questions. 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 HEPPAS. And I guess, how do you think now about the appropriate jumping-off point for doing a study in HEF-PEF with one of the myosin activators? And I guess, really, how does 586's movement into the clinic, I guess, either complicate or complement that strategy? Thank you.
spk11: Yes, so I'll start and turn it over to Fatty, but our movement of 586 into the clinic underscores our enthusiasm for myosin inhibition in patients with HEF-PEF who have hypercontractal ventricles. What you're seeing in NHCM, I should say what we're seeing in NHCM and you'll see on Sunday, we believe augers well for this mechanism in certain patients with HFPAF as will be now able to be explored with 586 as it moves forward. So I'll turn it over to Fatty to speak to what in particular we see in NHCM as reads on those patients with HFPEF.
spk06: Hi, Carter. You know, 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 with 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 an 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 may be less complicated in terms of making it available in that population in the long term.
spk11: 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 Afikampton. And more of that and why and how that may afford potential advantage and half path will come over time.
spk15: Thanks, guys.
spk11: Thanks, Carter.
spk12: Thank you. One moment for our next question. And our next question is from Tessa Romero with JPMorgan. Your line is open.
spk14: Yeah, good afternoon, Robert and team. Thanks so much for taking our questions. So, one commercial question for me. Can you talk a little bit about your market intel and what are the attributes about ASI Kempton'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.
spk11: 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, Afikampton versus Mavicampton. We think BMS is doing a good job with Mavicampton 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 Afikampton and where its profile may be enabling of an expansion of the category, and I'll ask Andrew to elaborate on that.
spk10: 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 a physician and patient experience of starting and staying on afecamptin 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 childbearing years, the amount of echoes that could be required, the type of REMS program. So these are real or could be real challenges and differences should, you know, 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 challenges issues in the marketplace, potentially, or differences, I should say, not issues. But obviously, we have to wait until phase three and what our data would bear out to see if we can truly differentiate.
spk11: You know, 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 be receiving the first-in-class compound. And we've designed Affy-Campton 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 Affy-Campton, 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.
spk14: Thank you for taking our question.
spk11: Thank you.
spk12: Thank you. One moment for our next question. And our next question is from Dane Leon with Raymond and James. Your line is open.
spk09: How are you doing? Hi. Thanks for taking the questions, and, you know, congrats on the progress heading to 23 now. Just maybe two 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 FDA, and how explicit they have been in terms of endpoints for pivotal, non-obstructive hypertrophic cardiomyopathy studies. Your peer, as is obvious, is using a KCCQ endpoint, change from baseline, and then 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, you know, if your experience kind of 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 does your team think you're going to cut it in terms of having that top line data before your end? Thank you.
spk11: So I'll answer the second part of your question and then ask Fatty 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 total Phase III study of NHCM, I think when we elaborate on that study, once it is underway, you'll see some similarities to the ongoing Phase III study with Mavikampton, but also some notable distinctions based on Kathy Campton has a different profile. But I'll ask Thadde to comment on sort of what's clinically meaningful with regard to some of these endpoints.
spk06: Well, I think the endpoints we can use in NHCM in a lot of ways mirror what we'll use in OHCM. Their function and their symptoms include peak VO2. They include KCCQ. They include NYHA class. And then secondarily, biomarkers and things that 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, you know, I think any of them are potentially meaningful and potentially approvable. KCCQ has been used to as an approvable endpoint in pivotal trials before, and obviously we see that BMS design incorporates that into their primary endpoint, and Peak VO2 is what we're using in Sequoia. You know, it's a magnitude. In general, people are looking for magnitudes that are five points or more in the KCCQ. That's a little arbitrary. You know, I think you have to look at the whole distribution and ask, 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. If others don't respond, it's 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. I think 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 NH and NHM.
spk11: You know, my hope is that you'll see data in the poster on Sunday that will be revealing as to how Affy Campton 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 elaborate on what would be a phase three study design in connection with duration of treatment and time to endpoints.
spk09: Excellent. Thank you so much.
spk11: Thank you.
spk12: Thank you. One moment for our next question. And our next question is from Jason Butler with JMP Securities. Your line is open.
spk19: Hey, Jason. Hi. Hey, Robert. Thanks for taking the question. Just one on the upcoming REL dissentive 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 timelines? Thanks.
spk11: Yeah, 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.
spk02: 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, it's designed in that way to mask a magnitude of change in ALS-FRS-R. Essentially, it's binary, so either upsizing or not. With respect to, you know, the timeframe for continuing enrollment, I think that's sort of, you know, better discussed when, you know, if that recommendation comes forward from the data monitoring committee. But enrollment's going very well. encourage ALS, and we don't expect a major delay in completing enrollment, even if this trial is upsized.
spk11: Maybe just to expand on that a little bit, I'll ask Fatih to comment on how the Data Monitoring Committee is being guided.
spk06: Yeah, 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 what I 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 assumed, which would certainly be a good scenario to be in. It could be a little less than you assumed. And if it's small enough, even as 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. 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, you know, the interim analysis in high-level terms.
spk11: Both 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 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.
spk02: Thank you.
spk11: Thank you.
spk12: Thank you. One moment for our next question. And our next question comes from Charles Duncan with Kantor Fitzgerald. Your line is open.
spk11: Hi, Charles.
spk21: 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 REL-D, and I apologize up front, 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 Reliverio impacted that? And third, again, going to Reliverio, is that in some ways changing or impacting the types of patients that are wanting to enroll in Courage ALS?
spk11: I'm going to be turning to Stuart. to answer these questions and anything Fadi wants to add on top of that. We're not commenting on the number of 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.
spk02: Hi, Charles. Thank you for the questions. With respect to the open-label extension, I think we can say that most of the patients are rolling over it into the extension, so that study is going well. 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. And furthermore, because this is now an approved therapy in North America, we are allowing patients even if they are treated with Reliviro to enroll in the trial. So any approved therapy is permitted as background therapy encourage ALS.
spk21: That's interesting. Okay. And then the last one in terms of enrollment that is being allowed, is that what you just said?
spk06: That's right. Yeah, they're allowed to enroll in the study if they're on Reliviro. That's by incorporated by amendment. It's similar to we allow patients on Daravone or patients on Rilizol to participate.
spk21: Yep. Yep. Got it. Thanks for taking the questions.
spk12: Thank you. Thank you. One moment for our next question. And our next question is from Justin Kim with Oppenheimer. Your line is open.
spk03: 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 clarification in terms of the second MAPLE study for afikantinin OHCM. Just wondering what type of blocking and tackling remains before initiating the study and if it's reasonable to expect
spk06: the initiation after completion of enrollment for Sequoia yeah I can comment on that I think thanks for the question you know 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 for different supplies, an afecamptin, a placebo for afecamptin, a metoprolol, and 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 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 this study start in the same timeframe that we see Sequoia winding down in terms of enrollment.
spk03: Okay, great. Thanks, and I look forward to the presentation this weekend.
spk11: Thank you.
spk12: Thank you. One moment for our next question. And our next question is from Salim Saeed with Mizzou. Your line is open.
spk11: Salim.
spk05: 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 afikantin, even if it's from the OLE? Whereas the powering here of 1.5 on peak VO2 change is based on what Explorer did, and mind you, that was at 1.4, and that the notion of afikantin 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?
spk11: Good questions. I am going to ask Paddy to answer them.
spk06: Also, Salim, I think you know probably that we have not reported it and the protocols for redwood and forest do not include exercise testing, peak VO2 testing, so we do not have any data per se. with that test and AFI-CAMPTN. 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, Sequoia is somewhat larger than Explorer was. The p-value for the peak VO2 at 1.4 was, you know, less than .001, and so we should be quite well-powered to see an improvement of 1.5, 1.4, you know, 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 nice proof of concept in terms of how that endpoint can be impacted by a cardiac myosin inhibitor, and so that helps de-risk, if you will, the primary endpoint of this trial.
spk05: Thanks, Patty. Will you provide the baseline at some point, you think, or...?
spk06: Probably right before you see the primary outcome. I don't think we'll be providing the baseline characteristics prior to the study's presentation.
spk05: Okay, got it. Thank you so much.
spk06: Thank you.
spk12: Thank you. One moment for our next question. And our next question is from Serge Bellinger with Needham Co. Your line is open.
spk11: Hey, Serge.
spk18: Hey, Robert. Good to hear you again this afternoon. Two questions on the AfriCanton 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 the a similar pace of enrollment for the MAPLE study as well as the other phase three trial in HCM, given that you can have three phase three trials running concurrently. And then secondly, in terms of the regulatory strategy, should we expect that both the MAPLE and the NHCM phase three trial to support separate SNDAs once they're complete? Thanks.
spk11: 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 III 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 Omicampt of McCarble, where there is a significant time lag from a U.S. submission to a European one. 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 approvals as would come internationally in more rapid succession. So I'll turn now to Fatih to address your first question regarding expected duration of enrollment in those second and third phase three studies?
spk06: Yeah, I think it's a question more related to the rate of enrollment, which I think we will, you know, 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, continue enrollment at the pace that we're seeing in Sequoia. And I think it's a little too early. I mean, we enrolled the NHCM cohort in Redwood quite briskly, and I'm optimistic we can do so in a Phase III trial as well. Hopefully that answers your question. Thank you. Thank you.
spk12: Thank you. One moment for our next question. And our next question is from Madhu Kumar with Goldman Sachs. Your line is open. Hello, Madhu.
spk15: Hey, how's 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 its potential kind of clinical impact and utility of Affy-Campden if this trial is successful? What kind of white space in the obstructive HCM space do you think 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
spk11: afi campton and withdrawal of other therapies within the kind of formal clinical trial setting yes so your question has implications both for the clinical profile but also the commercial profile and maybe fatty can start uh talking about what could be the value of demonstrating effects of only rather afi campton relative to metoprol but then andrew should also comment you know the uh
spk06: The Maple HCM study is something our investigators and steering committee members are really excited about. You know, they view it as a critical question to have data that support, if you will, using apicamptin as first-line therapy. The real question is what benefits do you get from beta blockers as monotherapy and And in general, you know, you do see reductions in gradient improvement symptoms. You don't see really any improvement in exercise capacity. And so how does that compare in a head-to-head study with afikantin, you know, 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, you know, structural remodeling occurs in the context of beta blockade. contrasted with cardiac myosin inhibition. So while that's not necessarily an approvable endpoint, it does speak to 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 to position this mechanism of action and both in their practices, but also in their guidelines.
spk10: The only thing maybe I'll add is around from a commercial perspective is 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, afecantin getting reimbursed. Does a patient need a step through? Does a 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 a payer community.
spk11: 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 Affie Campton.
spk15: Great, thanks. And we also look forward to seeing you this weekend. Ben Yee is on me.
spk06: Thank you. Very good.
spk12: I'm showing no further questions at this time. I would now like to turn the conference back to Robert Blum for closing remarks.
spk11: Thanks everyone for joining us, not just on this call today, but also on the call this morning. I realize this call has gone over an hour, so we'll be brief in these concluding remarks. I'll just simply say that yes, we are disappointed as it relates to the FDA action pertaining to Omicampt and McCarble. But under every scenario, 2023 was always going to be a year about doubling down on Affycampton and committing to a higher investment spending on Affycampton and an expanded development program for Affycampton. Not to say it's not also important for REL Deceptive and our early pipeline. But I do think we're aligned with shareholder expectations that AFI Campton 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 OMI Camptive 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 Affy Camden. 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.
spk12: This concludes today's conference call. Thank you for participating. You may now disconnect.
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