Q4 2022 Cytokinetics Inc Earnings Call

Speaker 2: Good afternoon and welcome, ladies and gentlemen to Cytokinetics fourth quarter twenty twenty two 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.

Speaker 2: 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.

Speaker 2: 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 Malik, EVP of R&D, will provide updates related to on the Kempton-McCarble and Asse Kempton.

Speaker 2: as well as other drug candidates comprising our early clinical development pipeline. Andrew Kallos, EVP and Chief Commercial Officer, will speak further about omecamptin macarbil and our specialty cardiology franchise strategy related to afecamptin. I'm Stuart Cooper, SVP and Chief Medical Officer.

Speaker 2: will provide an update on real disemtive. Robert Wong, VP and Chief Accounting Officer, will provide a financial overview of the past quarter. And Qing Jia, SVP and Chief Financial Officer, will discuss our 2023 financial guidance and corporate development strategies. Finally, Robert Blum will provide closing comments.

Speaker 2: 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.

Speaker 2: Additional information concerning factors that could cause their 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.

Speaker 3: We undertake no obligation to update any forward-looking statements after this call. And now I will turn the call over to Robert.

Speaker 4: Thank you, Diane, and thanks to all for joining us on the call today.

Speaker 4: The fourth quarter of 2022 was productive across our pipeline with continued progress being made through the beginning of this year.

Speaker 4: Beginning with Omicamtum of McCarble 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.

Speaker 4: in adults with chronic heart failure with F-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 omicanthemocarbola are required to establish substantial evidence of effect for the treatment of F-REF with benefits that outweigh the risks.

Speaker 4: 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 omecamtivacarbol in the United States.

Speaker 4: However, as mentioned this morning, we have no plans to conduct an additional clinical trial of Omicamtum carbo and our focus remains on the development program for Affy-Campton.

Speaker 4: 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 Omicamp to McCarble. Our commercial infrastructure has also been designed and developed to support social and economic development of our cities. While the move does not render itself as theELD shall, it is certainly related to our healthcare spending and health security metrics in which you should 36

Speaker 4: with the ability to pivot to focus on Afikamtin 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 Omecamtamcabral.

Speaker 4: in other countries and as may provide support to corporate development and business development activities. As mentioned previously, we believe in the science underlying Omicamp to Macarble and the demonstrated clinical evidence.

Speaker 4: to potentially benefit patients with advanced and worsening heart failure. With that said, however, we will not bet the company on omecamtum macarville and ours is a broad pipeline on novel muscle biology-directed drug candidates.

Speaker 4: Soto Kinetics is well positioned to press forward with AFI-Campton 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 AFI-Campton progressed forward.

Speaker 4: 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.

Speaker 4: later this year in Q4.

Speaker 4: Concurrently, we have plans to substantially expand the development program for Afecamtin by beginning two new phase 3 clinical trials in 2023, one in OHCM with Afecamtin as monotherapy and one in NHCM. Stuart will elaborate for Rel-Defemptive.

Speaker 4: Patient enrollment continued to encourage ALS following the first interim analysis that occurred last quarter and respect the data monitoring committee to conduct the second interim analysis for the ongoing trial in the second quarter of this year. We believe RelDef can represent an entirely new pharmacology

Speaker 4: for ALS patients underserved by the lack of a muscle-directed therapy.

Speaker 4: Entering 2023, SOTO 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 deal-making and prudent investment spending.

Speaker 4: 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.

Speaker 4: And despite the setback for Omecamp 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 Fadi.

Speaker 5: Thanks Robert. Before we move on to the Athei Campton, I want to express my disappointment in this outcome for on the Campton Macarble.

Speaker 5: and also share my gratitude to the many employees, investigators, and patients who contributed to the development program over the years.

Speaker 5: While we continue to work with FDA and assess the next steps for omecamp to McCarble.

Speaker 5: In the fourth quarter, the European Medicines Agency accepted the marketing application for omacamtiv macarbil. 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 omacamtiv macarbil.

Speaker 5: We will continue to pursue international approvals from Camp de Macarble as we assess its future for the program in the US.

Speaker 5: Moving on to Appicampton, we made excellent progress in the fourth quarter.

Speaker 5: 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.

Speaker 5: with results expected in the fourth quarter of the year.

Speaker 5: During the quarter, we also completed enrollment in cohort 4 of Redwood HCM.

Speaker 5: We plan to share data from this cohort in non-obstructive H&M patients in a poster session at the American College of Cardiology, Scientific Sessions, this coming weekend. Setting up, setting us up for advancement into a pivotal Phase III clinical trial in patients with non-obstructive NHM.

Speaker 5: in the second half of the year. Related to Redwood HCM, during the quarter, we were also pleased to announce the full results from Co-Works one and two of Redwood HCM were published in JAC, elaborating on its next in class profile.

Speaker 5: In addition, we further preparations for our second phase III clinical trial of afecamtin as monotherapy compared to metoprolol in patients with obstructive HCM.

Speaker 5: We're calling the trial MAPLE HCM, which stands for Metoprolol versus Afecamtin in patients with left ventricular outflow tract obstruction an exercise capacity.

Speaker 5: 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.

Speaker 5: MAPLE HCM is a phase 3, multi-center, randomized, double-blind, active comparator trial in patients with symptomatic OHCM and elevated LVOT gradients.

Speaker 5: It is expected to enroll approximately 170 patients. The primary endpoint is change in PQCO2 assessed by CPET from baseline to week 24.

Speaker 5: Secondary endpoints include change in NYHA class, KCCQ, NT-proBNP, and measures of structural remodeling.

Speaker 5: We look forward to sharing more details about the trial upon the opening of enrollment.

Speaker 5: 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 Hep Rep and other types of heart failure, such as right ventricular failure resulting from impaired cardiac contractility.

Speaker 5: 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.

Speaker 5: We expect to share data from the Phase I trial in the second half of the year.

Speaker 5: Additionally, more recently we presented preclinical data related to a newer compound.

Speaker 5: Ck4021586 or Ck586

Speaker 5: 402-1586 or CK586. It's another cardiac myosin inhibitor.

Speaker 5: 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. AntimBER eclipse

Speaker 5: We look forward to advancing this compound into clinical development during this first half of the year.

Speaker 5: Despite the CRL for omacamptomacarbil, we have three other cardiovascular drug candidates advancing in development.

Speaker 5: led by Api Campin in the pivotal phase three clinical trials, COIA HCM.

Speaker 5: Our cardiovascular franchise emerging from our sarcomere-directed research continues to deliver on the promise of new potential medicines for patients.

Speaker 5: With that, I will turn the call over to Andrew to speak about omecamptomacarbol and our specialty cardiology franchise strategy.

Speaker 4: 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 dated on the approval of Omicamp to the Carville.

Speaker 4: As a result of our receiving a CRL, we will dial back on what would have been our commercial spending had FDA approved on the campus of McCarble.

Speaker 4: With that said, the commercial readiness infrastructure that we have established would always develop with an eye toward a cardiovascular franchise strategy and the future launch of AFI-Campton and additional cardiac muscle modulators.

Speaker 4: Over 90% of our commercial team had responsibilities that are not solely dedicated to Omicamp to McCarble. Our current team is predominantly the same team needed to support African. 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 Omicamp.

Speaker 4: 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 Afecanton. Last quarter, we completed an initial go-to-market strategy for Afecanton.

Speaker 4: 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 Appy Hampton across potentially multiple indications.

Speaker 4: Cardiac myosin inhibition is proving to be an important for the treatment of patients with OHCM, and we expect that we'll propel Cytokinetics to be a global specialty cardiovascular company leading with Apicampin, and assassinating our important planning and executing in both 2023 and in 2024.

Speaker 4: With that, I will turn the call over to Stuart to provide an update on rural deceptive. Thanks Andrew.

Speaker 5: On the neuromuscular side, Reldacensib remains a key late-stage program for our company. In the fourth quarter, we proceeded with patient enrollment in CURA-JLS, with now over 450 patients enrolled to date, or more than three-quarters of our target patient enrollment.

Speaker 5: We are on track to complete enrollment in the second quarter of 2023 and readout results in 2024.

Speaker 5: During the quarter, we announced the continuation of COURAGE ALS following the first interim analysis for futility conducted by the Data Monitoring Committee.

Speaker 5: which reviewed unblinded data from the trial. We expect the second enter right now to take place in the second quarter, which will also assess refutility 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,

Speaker 5: We continue to enroll patients who completed COURAGE ALS.

Speaker 5: into COURAGE-ALS-OLE, or the open label extension. And we advanced plans for a managed access program for relative incentives to be available to patients who have completed any of our previous ALS trials, including Vitality ALS, the phase three clinical trial and tier-exemptives.

Speaker 5: Fortitude ALS, phase 2 clinical trial of relative symptoms. Finally, late last year, we were pleased to present data at the 33rd International Symposium on ALS MND from an analysis of Fortitude ALS.

Speaker 5: I find that patients predicted survival risk score was strongly correlated with decline in ALS FRS-R.

Speaker 5: and suggesting that the inclusion criteria selected for pure JLS 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.

Speaker 6: And with that, I will turn it over to Robert Wong. Thanks, Stuart. We ended the fourth quarter with approximately $830 million in cash and investments.

Speaker 6: Our revenue in Q4 2022 came primarily from Estellas to co-fund Courage ALS.

Speaker 6: 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.

Speaker 6: 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 O'McCampden-McCarvel. And our increase in personnel related costs.

Speaker 6: including stock-based compensation. And now Ching will review our financial outlook, 2023 Guidance and Corporate Development Strategies.

Speaker 7: Thanks, Robert. Today we announced our financial guidance for 2023.

Speaker 7: The company anticipates revenue will be approximately 5 million, driven by a stylish reimbursement of the cost of courage ALS.

Speaker 7: 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 Abbicamten in non-obstructive HCM.

Speaker 7: Operating expenses will be in the range of $420 to $450 million, and net cash utilization will be approximately $350 to $375 million.

Speaker 7: 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.

Speaker 7: With our having received a CRL from the FDA, we will not incur a substantial portion of cost.

Speaker 7: for what would have been our planned spending to launch on Canton-Macarbo in the United States.

Speaker 7: a majority of which was purposefully gated on potential FDA approval.

Speaker 7: As Andrew mentioned earlier, related to Omikentum and Carbo, 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 input structure is

Speaker 7: could be redeployed to support potential global launch planning for AFI Kempton.

Speaker 7: Looking to other programs and spending this year, of our anticipated 150 million in clinical development spending in 2023, roughly 60 percent will be allocated to development program of Appy-Kimpton. As we have done in the past, we aim to end

Speaker 7: 2023 was more than two years of cash runway. We remain in a strong cash position.

Speaker 7: But as a testament to our goal of maintaining multiple levers for accessing capital,

Speaker 7: 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 Baum.

Speaker 7: pursue additional business development and corporate development deals this year. And with that, I'll turn the call back over to Robert Bond. Thank you, Qing.

Speaker 4: While things didn't go the way we had hoped for Omicanto-Macarble, with our having received a CRL from FDA, 2022 was still a year of very meaningful progress, with our company maturing and transforming.

Speaker 4: We are familiar with overcoming challenges at South Ocathedics. And as Andrew said, we plan for this scenario and we are prepared to maintain our momentum without pause.

Speaker 4: As we assess potential next steps for Omicamta and McCarville in the United States, in 2023, our priority remains focused to AFI-Campton, which is advancing in a broadening development system, but several important near-term milestones this year.

Speaker 4: 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 Afecamtin. And in addition, we look forward to results from Sequoia HCM later this year.

Speaker 4: 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.

Speaker 4: RELL Decemptive 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.

Speaker 4: Our future remains bright, and as always, we appreciate the support of our shareholders. Now I'll recap our upcoming milestones for 2023. For only Camden McCarble, we expect a request of meeting with FDA to understand what may be required.

Speaker 4: to support potential approval of Omicapta macarville in the United States.

Speaker 4: And we expect to engage with EMA regarding the MAA for the treatment of HIF-REF.

Speaker 4: For Afecampton, we expect to present data from cohort four of Redwood HCM and data from 48 weeks of treatment with Afecampton in Forest HCM at the American College of Cardiology's 72nd Annual Scientific Sessions this weekend.

Speaker 4: And we expect to complete patient enrollment in Sequoia HCM in Q2 2023 with results expected from that trial in Q4 2023.

Speaker 4: We expect to begin Maple HCM, the second phase three clinical trial of Aficamten, as monotherapy in patients with obstructive HCM in Q2, 2023. And we expect to begin a phase three 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.

Speaker 4: 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. 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, will we compile the Q&A roster? If you see the official

And our first question is from Yasmin Rahimi with Piper Sandler. Your line is open.

Good afternoon. Good afternoon, Robert, and I'm deeply sorry for the outcome of Omicamtif.

I guess my one question is directed to Fadi 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.

Thank you, Yasmin, for that. You know, I, um...

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 IWRS system that dispenses drug. And in order to dispense drug, the sites have to enter in the site red ejection fraction. And that's done by...

cardiologist that's not part of the study team and is blinded to study treatment.

So we don't get notified if the S dropped below 50%. If somebody's ejection fraction dropped below 40%,

That would require a termination of treatment and that would become a noted event to which we would become privy to.

We're pleased with how things are going and maybe I should just put it put it that way Thank you so much Betty for the call. I really appreciate it and I'll jump back into the queue.

Thank you. Yes. Thank you. Thank you. One moment for our next question. And our next question is from Joe Pantanis with HC Wainwright. Your line is open.

Hey, Joe.

Hey guys, good afternoon. Thanks for taking the question. So curious, so Robert this morning you talked about how it's you know early to discuss and the iterative process with regard to Omicamtiv in Japan and the EU potential there. I was just curious if you had any commentary about the approach that Jiejing is taking and if there's any differentiation.

Yes, so I should allow Xi Jinping 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 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.

Appreciate the comment.

Thank you. One moment for our next question.

And our next question is from Jason Zemanski 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 AFA Campton, any sense on how one could potentially operationalize?

that we see within the Sequoia Phase III design. Thanks.

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 Fatih to elaborate. 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 views and things like that and echocardiograms that can take longer, but that'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.

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. 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 AFI-Campton. I think Fadi may have another comment to make. A follow-up, I mean I think...

You know, 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 C. Rick Rieba, Diver Kondo, with true of securities. Your line is open.

Our next question is from C. Rick Reba, Diva Conda with Truist Securities. Your line is open. Hi everyone.

Hi, I'm one for Kripa. So with Omecamp, 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. Yeah, 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 only Camp de Macarble.

is not something for which we're yet ready to communicate publicly. What I will say is divesting Omecamtumacarbol 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 Omecamtumacarbol.

I don't think that is something that we have high confidence is in the interest of science or patience. So what we may do instead is around partnering on the Camp to McCarvel 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 Omicamp to McCarble and that's something that I think is more likely going to be something that moves the needle for Sado Kinetics. Thank you. Thank you. Thank you. When moment for our next question. Our next question is from Carter Gold with Barclays. Your light is open. 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 talked about the non-obstructive data.

being sort of a pilot for moving into HEPF. And I guess, how do you think now about the appropriate jumping off point for doing a study in HEPF with one of the milestone activators? How does 5-8-6 movement into the clinic either complicate or complement that strategy? Yes, so I'll start and turn it over to Fadi, but our movement of fire...

day. We believe auger's well for this mechanism in certain patients with F-PATH as will be now able to be explored with 5-8-6 as it moves forward. So I'll turn that over to FADDI to speak to what in particular we see in NHCM as reads on those patients with F-PATH.

Hi, Carter. We laid this strategy out in 2018 at an R&D day, which is that OACM represents the vanguard of application for a cardiac myosin inhibitor.

with obvious extension to any CM but then any CM provides a genetic model be 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 that can

And the entry of 5-8-6 into the clinic enables us to potentially use a different molecule in heart failure with preserved ejection fraction as you know, maybe.

be 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 Aathy Campton.

and more of that and why and how that may afford potential advantage and how fast path will come over time.

and more of that and why and how that may afford potential advantage and have tough will come over time. Thanks, Carter.

Thank you. One moment for our next question. And our next question is from Tessa Romero with J.P. Morgan. Your line is open. 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...

acicampans emerging profile that may be the most kind of needle moving for the positions 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. Afty Campton 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 AFI Campton 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 questions. Probably the key differences that we're hoping for at least in terms of differentiation really comes down to healthcare utilization.

as well as a physician and patient experience, both starting and staying on as he can't and 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 Calbearing years, the amount of echoes that could be required, the type of rents programs. So these are real...

Or could be real challenges and differences? Should one product have and require a 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 till phase 3 and what our data would bear out the shape 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 AFI Campton very much to be enabling of a broad therapeutic window, faster onset, faster reversibility where that to be required. And as such, that could be supportive of the use of AFI 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 myocin inhibitor for their patients. Thank you for taking our question. Thank you. Thank you, one moment for our next question.

Next question is from Dame Leon with Raymond and James. Your line is open. Hey, David. Hi.

Next question is from Dame Leon with Raymond and James. Your line is open. Hi, thanks for taking the questions and

Congrats on the progress, saying the 23 now. Just maybe two for me that have been topical for a lot of investors recently. Maybe if you could have a pine in terms of your discussions with the cardiovascular team over at FDA and how explicit they have been in terms of end points for pivotal non-obstructive hypertrophic cardiomyopathy studies, your peer is obvious. 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 seemed to 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. I then roll them in.

before Sequoia is still ongoing. I think some people are asking right now, how close does your team think you're gonna cut it in terms of having that top line data before your end? Thank you. So I'll answer the second part of your question and then ask Fadi 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 but 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 three study of NHCM, I think when we elaborate on that study once it is underway, you'll see some similarities to the ongoing phase three study with Mavicampton, but also some notable distinctions based on ATHY Campton has a different profile.

But I'll ask Sadi to comment on sort of what's clinically meaningful with regard to some of these endpoints. Well, I think the endpoints we can use in NHCM in a lot of ways mirror what we'll use in OHCM. They include their function and their symptoms. They include peak VO2. They include KCCQ. They include NYHA class.

Minimum 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...

The question might be what might you order first and what might you focus on? And I think any of them are potentially meaningful, intentionally approvable. KCCQ has been used to as a approvable endpoint and pivotal trials before. And obviously we see the BMS design incorporates that into the primary endpoint.

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 others don't respond. You know, 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. So...

and may be received in NHCM. And again, our mind you are 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 three study design in connection with duration of treatment and time to end points.

in NHCM. And again, our mind you are 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 three 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.

Hi, Robert. Thanks for taking the question. Just one on the upcoming Rel Disceptive 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?

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.

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 send to a mask, sort of a magnitude of magnitude of...

change in ALS-SFR. So essentially it's binary. So I've been up sizing or not. With respect to the timeframe for continuing enrollment, I think that's sort of better discussed when

if that recommendation comes forward from the data monitoring committee. Enrollment is going very well in Courage ALS and we don't expect a major delay in completing enrollment even if the trial is upside.

Maybe just to expand on that a little bit, I'll ask Fadi to comment on how the data monitoring committee is being guided. Yeah, so I think the...

You know 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-myth scenario You've you've assumed a treatment effect you power a study based on that assumption the trial progresses and then the treatment effect may be larger than you assume 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, it even 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 increments, 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 the interim analysis in high-level terms. Both of those are possible outcomes. They may not be probable.

But we thought it was important to lay them out there. There is a 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. Thank you. Thank you. Thank you.

Thank you. One moment for our next question. 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...

5 percent, secondly, with regard to the ongoing OLE, do you have a sense of the role over and persistence and has relibrary impact at that? And third, again, going to relibrary, 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 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 a 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 still expect results next year if that helps you put it into a short code. Then I'll turn to Stuart, maybe to answer the other two questions.

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 put it into a short code. Then I'll turn to Stuart maybe to answer the other two questions. Thank you for questions. Thank you for questions.

With respect to the open label extension, I think it's, we can say that most of the patients are rolling over it into the extension, so that study is going well.

The impact of delivery, not surprisingly, there has had some impact in terms of enrollment in North America. 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 delivery out to enroll in the trial. So any approved therapy is permitted as background therapy encourage ALS. That's interesting. Okay. Thank you.

And then the last one in terms of enrollment that is being allowed is that what you just had. That's right. Yeah, they're allowed to enroll in the study if they're on real or zero. That's by Incorporated by an admin. Yeah. Okay.

It's similar to we allow patients on the daryvone or patients on really as all to participate. Thanks for taking the questions.

It's similar to we allow patients on their own or patients on really as all to participate. Thanks for taking the questions.

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 clarification in terms of the second maple study for acicampin in OHTM. What type of blocking and tackling remains before issuing the study and if it's reasonable to expect the initiation after completion of enrollment for Sequoia? Yeah, I can comment on that. I think thanks for the question. It's a complicated study to start from the point of view of drug supply and things as we said before, we are packaging and labeling and manufacturing for different supplies of an acicampin, a placebo for acicampin, a metoprolol and a metoprolol for acicamp, a placebo for metoprolol.

So it's applied 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, the FOIA 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.

Hi, guys. Thanks for the question. I guess one for me in Sequoia is folks are to pivot on handicap in this trial. This site at Kinetics has any data at all on KGBO2 change for APA Captain even if it's from the OLE.

Where's the powering here of 1.5 on TQ-2 changes based on what exploded and mining that was at 1.4 and that the notion of African-Canton is just a better product and just quickly related to that. Will you actually give us the baseline TQ-2 prior to read out so we can handicap the good questions I'm going to ask fatty to answer them.

Also, Sillim, I think you know probably that we haven't reported it and the protocols for Redwood and Forest don't include exercise testing, peak care, two testing. So we don't have any data per se with that test in Afi-Campton. You know, 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.

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 mice and inhibitor. And so that helps to be risk if you will, the primary endpoint of this trial.

Thanks, Vady. Will you guys believe provide the baseline at some point, you think, or? Probably right before you see the primary outcome. But you have to think via. Okay. Now I don't think we'll be providing the baseline characteristics prior to the studies, you know, presentation. Got it. Thank you so much. Thank you.

Thank you. Thank you. One moment for our next question. And our next question is from Surge Belinger with Needham Co. Your line is open. Hey, Surge. Hey, Robert. Here you go. In the afternoon, two questions on the African and the States 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 from the Sequoia trial.

Yes, so I'll answer the second part first.

Our registration strategy, the critical path is paved with Sequoia HCM and will 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 OME Campdom, the McCarble where there is a...

significant time lag from a US 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 Fadi to address your first question regarding expected duration of enrollment in those second and third phase three studies. Yeah, I think it's more related to the rate of enrollment, which I think we will, you know, these trials are a little different. So with regard

that we've seen in Sequoia. And I think it's a little too early. I mean, we've enrolled the NHCM cohort in Redwood quite briskly and I'm optimistic we can do so in a phase three trial as well.

Hopefully that answers your question. Thank you. Thank you. Thank you. One moment for our next question. And our next question is from Madhu Kumar. The Goldman Sachs. Your line is open. Hey, that's good. Thanks for taking our question. Thank you.

kind of falling up on Maple HCM. I'm going to curious how should we think about this trial and it's the potential kind of clinical impact and utility of Acicampton if this trial successfully. What kind of white space in the obstructive HCM space do you think?

this drug, this trial uniquely addresses. And I guess kind of sitting back to the earlier data from last year about drug withdrawal. How do you think about that on the forward and the potential idea of monotherapy of affi-campton 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 if I could start talking about what could be the value of demonstrating effects of Ome-Rather-Africampton relative to Betoeprol, but then Andrew should also comment. You know, the Maple exam 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 to support, if you will, using AFI Campton 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 symptoms. You don't see really any improvement in exercise capacity. And so how does that compare and ahead to head study with AFI Campton?

It was made eventually support, at least from a scientific perspective, its implementation is first-line therapy. The other thing is to look at how structural remodeling occurs in the context of beta-block aid contrasted with cardiac mice and inhibition. So, well, 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 both in their practices but also in their guidelines. The only thing I'll add is around from a commercial perspective, 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, if you can't then get getting reimbursed.

you know, 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 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 AFI Camden. Great, thanks. And we also look forward to seeing you this weekend, if you want to keep your interviews on me.

Thank you. Very good. I'm showing no further questions at this time. I would now like to turn the conference back to Robert Blum for closing remarks. Thank you,

So 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 Omicamtum and McCarble, but under every scenario, 2023 was always going to be a year about doubling down on Afecamtin and committing to a higher investment spending on Afecamtin.

and an expanded development program for ATHY Campton. Not to say it's not also important for Reldissemptive and our early pipeline, but I do think we're aligned with shareholder expectations that ATHY Campton represents an opportunity for which the return on investment should be predictably higher and we recognize that and that's where we're gonna be focused. We're not gonna be providing play-by-play with regard to OMI Campton now.

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

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You oh.

I you, I.

Good afternoon and welcome ladies and gentlemen to the site of Kinetics 4th quarter 22 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. Diane Weiser, Senior Vice President of Corporate Communications and Investor Relations and Investor Relations

as well as other drug candidates comprising our early clinical development pipeline. Andrew Kallos, EVP and Chief Commercial Officer, will speak further about omicamptin macarbil and our specialty cardiology franchise strategy related to afecamptin. Stewart Kupfer, SVP and Chief Medical Officer, will provide an update on rel desemptive.

Robert Long, VP, and Chief Accounting Officer will provide a financial overview of the past quarter, and Qingda, SVP and Chief Financial Officer will discuss their 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, contains statements that relate to future events and performance rather than historical facts and constitutes 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 statement 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. A fourth quarter of 2022 was productive across our pipeline with continued progress being made through the beginning of this year.

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 half-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 Omicamp to Macarbel are required to establish substantial evidence of the effect for the treatment of half-ref with benefits that outweigh the risks. As we stated in our call this morning, we expect your request of meeting with FDA in order to understand if-

was gated on the potential approval of Ome Campton Maccarbel. Our commercial infrastructure has also been designed and developed with the ability to pivot to focus on AFI Campton 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 Omecamtamocarbil in other countries and as may provide support to corporate development and business development activities. As mentioned previously, we believe in the science underlying Omecamtamocarbil 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 Omecamtamocarbil and ours is a broad pipeline on novel muscle about biology directed drug candidates.

Cytokinetics is well positioned to press forward with Afecampton 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 Afecampton 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 NHCM 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 AFI-CAMPTEN by beginning two new phase three clinical trials in 2023, 1 in OHCM with AFI-CAMPTEN as monotherapy and 1 in NHCM. As Stuart will elaborate for relative patient enrollment continued in Courage ALS following the first intraminalysis that occurred last quarter and respect the data monitoring committee to conduct the second intraminalysis for the ongoing trial in the second quarter of this year. We believe Reldefemtive can represent an entirely new pharmacology for ALS patients underserved by the lack of a muscle directed therapy.

Entering 2023, the Auto 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 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 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 Omicampton Maccarbo, 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 Fadi. Thanks Robert. Before we move on to Kathy Campton, I want to express my disappointment in this outcome for on the Campton Macarble. 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 step for on the Campton Macarble.

In the fourth quarter, the European medicine agency accepted the marketing application for Omicamp to McCarble. As Xi-sheng 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 Omicamp to McCarble. We'll continue to pursue international approval for Omicamp to McCarble as we assess its future for the program in the U.S. We'll be on the AFI campton. 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 the fourth quarter of Redwood HCM.

We plan to share data from this cohort in non-obstructive H&M patients in a poster session at the American College of Cardiology, Scientific Sessions, this coming weekend. Setting up, setting us up for advancement into a pivotal phase 3 clinical trial in patients with non-obstructive H&M in the second half of the year.

Related to Redwood HCM, during the quarter we were also pleased to announce the full results from the COERS1 and 2 of Redwood HCM were published in Jack, elaborating on its next in class profile. In addition, we further preparations for our second phase 3 clinical trial of Atheicampton as monotherapy compared to Metoper Law and patients with obstructive HCM. We're calling the trial Maple HCM.

which stands for Motoprolol versus AFI-Campton 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 multi-center randomized double-blind active comparator trial in patients with symptomatic OHCM, an elevated LVOT gradients. It is expected to enroll approximately 170 patients.

activator in development for the potential treatment of patients with HAPRAP 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 I 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 mice and inhibitor. CK586 has a mechanism of action that's distinct from apicampton and its advancement affords us the potential explorer the therapeutic application of cardiac mice and inhibition to treat certain types of heart failure with preserved ejection fraction or 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 omecamptin macarbil, we have three other cardiovascular drug candidates advancing in development, led by apicamptin in the pivotal phase three 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 omecamptomacarbol and our specialty cardiology franchise strategy. 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 on the captive macarbole. As a result of our receiving of CRL, we will dial back on what would have been our commercial spending had FDA approved on the captive macarbole. With that said, the commercial readiness infrastructure that we have established would always develop with an eye toward a cardiovascular franchise strategy and the future launch of Acid Campton and additional cardiac muscle modulator.

Over 90% of our commercial team had responsibilities that are not solely dedicated to OMACaptives McCarble. Our carrot team is predominantly the same team needed to support ASECaptain, 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 Aficantan. 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 Aficantan. Last quarter, we completed an initial go-to-market strategy for Aficantan.

and progress our commercial readiness plans. We are within the window in which much work needs to be done to prepare for potential global launches of Appi-Campdon across potentially multiple indications. Cardiac-Mias and inhibition is proving to be an important for the treatment of patients OHM, and we expect that Wulpa-Pell cytokinetics to be a global, especially cardiovascular company leading with Appi-Campdon, and assassinating our important planning and executing in both 2023 and 2024. With that, I'll turn the call over to Stewart to provide an update on World Discept.

first interim analysis for futility conducted by the Data Monitoring Committee, which reviewed unblinded data from the trial.

We expect the second intranet 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 Reldissemptive to be available to patients who have completed any of our previous ALS trials, including Vitality ALS, Phase III Clinical Trial and Tera Assemptive and Fortitude ALS, Phase II Clinical Trial of Reldissemptive.

Finally, late last year, we were pleased to present data as a 33rd International Symposium on ALS M&D. From an analysis of fortitude ALS, China's patients predicted survival risk score was strongly correlated with decline in ALS-FR. And suggesting that the inclusion criteria selected for purge 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 Long.

Thanks, Stewart. We ended the fourth quarter with approximately 830 million in cash and investments. Our revenue in Q4 2022 came primarily from a stela to co-fund Courage ALF. 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 the co-HCM and Courage ALF.

and for our other cardiac muscle inhibitor and early research programs. Our fourth quarter 2022 GNA 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 Omicampdiv Macarble and our increase in personnel related costs including stock-based compensation. And now, Cheng 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 a dollar's reimbursement of the cost of courage ALS. In addition we expect to receive 50 million dollars in a milestone payment from Royalty Farma upon the start of

the pivotal phase three clinical trial of Abd Kempton in non-obstructive HTM.

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 plan spending to launch on the Canton Macarvel in the United States. A majority of which was purposefully gated on potential FDA approval.

As Andrew mentioned earlier, related to Omicanto McCarvel, 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 of a significant majority of our commercial input structure.

could be redeployed to support potential global launch planning for AFI 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 was more than two years of cash runway. We remain in a strong cash position, 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 Bonne. Thank you, Qing. While things didn't go the way we had hoped for Omecantra Macarble, without 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 as South O'Kathetics. And as Andrew said, we plan for this scenario and we are prepared to maintain our momentum without pause. As we assess potential next steps for Omicampton, Macarbel in the United States, in 2023, our priority remains focused to Affy Campton, which is advancing in a broadening development program, but 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 AFI Campton. 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 mice and 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. Reldissimtive 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 only Camp Democarble, we expect a request of meeting with FDA to understand what may be required to support potential approval of only Camp Democarble in the United States. And we expect to engage with EMA regarding the MAA for the treatment of half-ref. For Athee Campton, we expect to present data from cohort 4 of Redwood HCM.

and data from 48 weeks of treatment with AFI Campton in forest HCM at the American College of Cardiology 72nd annual scientific sessions this weekend. And we expect a 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 AFI Campton.

as monotherapy in patients with obstructive HCM in Q2 2023, and we expect to begin a phase 3 clinical trial of AFI-CAMPTON in non-obstructive HCM in the second half of 2023. And also, we expect to advance our US Go-to-Market Strategy for AFI-CAMPTON during 2023.

For CK136, we expect data from the Phase I study of CK136 in the second half of 2023. For Reldefemted, we expect the Data Monitoring Committee to conduct the second interim analysis from Courage ALS in Q2 2023. We expect a complete patient enrollment and Courage ALS.

also in Q2 2023 with results expected in 2024. And for our pre-clinical 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.

As a reminder to ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please limit yourself to one question. Please stand by where we compile the Q&A roster.

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 Ome Camtist. I guess my one question is directed to Fadi in regards to Sequoia.

for person. Thank you, Yasmeen, for that. You know, 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 IWS system that dispenses drug. And in order to dispense drug, the 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 of the F-drop will of 50%. If somebody's ejection fraction dropped below 40%.

for our next question.

And our next question is from Joe Pancinus with HC Wainwright. Your line is open.

Good job. 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 regards to OmaCampdiv in Japan and the EU potential there. I was just curious if you had any commentary about the approach that G-Ging is taking and if there's any differentiation.

Yes, so I should allow G-Zing 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 OME CAMP to Macarble 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.

or 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 Zamansky with Bank of America. Your line is open. Thank you so much for taking our questions. Curious as you think about a go-to-market strategy for Africa Campton, 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 3 design. Thanks. We're so as you probably can well appreciate.

The only things you need to assess are the gradient and the ejection fraction. You do lots of other use and things like that and echo cardiograms that can take longer, but that's really up for the top to the site to decide on how to implement that.

With regards to your question about dosing, I should be clear that every two weeks schedule we employ 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 weigh at least two weeks before making a dosing change. And it's up to the patient and the position of 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 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 AFI-Campton. I think Fadi may have another comment to make. It's a follow-up. I mean, I think...

You know, 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 if they maybe have been living with their disease for a long time. So we think that 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.

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 that 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 C. Rick Rieba, Deva Kondo, with true of securities. Your line is open. Thank you. Thank you, Sean.

Hi, Greg from Zinichand, I'm on for a Kripa. So with Omicamp, you said that you don't want to run another trial in US. So just wondering, what is the likelihood of a few, either devastating this asset to a company that already has a franchise in place or has a capital? And what is it 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 Omicamp to Macarble is not something for which we're yet ready to communicate publicly. What I will say is divesting Omicamp to Macarble 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 Omicamtumma carbulin. 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 Omicamtumma carbulin, 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 OME Camp to McCarble. 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. Our next question is from Carter Gold with Barclays. Your light is open. 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 talked about the non-instructive data being sort of a pilot for moving into half past.

And I guess, how do you think now about the appropriate jumping off point for doing a study in HEPF with one of the milestone activators? And I guess really, how does 586's movement into the clinic, I guess either complicate or complement that strategy?

Yes, so I'll start and turn it over to Fadi, but our movement of 586 into the clinic underscores our enthusiasm for myosin inhibition in patients with F-PEPF who have hypercontractal ventricles. What you're seeing in NH-CM, I should say what we're seeing in NH-CM and you'll see on Sunday.

We believe augers well for this mechanism in certain patients with F-PATH as will be now able to be explored with 5-8-6 as it moves forward. So I'll turn that over to Fadi to speak to what in particular we see in NHCM as reads on those

patients with FPEF. Hi Carter. We laid this strategy out in 2018 at an R&D day, which is that OACM represents the vanguard of application for a cardiac mice and inhibitor with obvious extension to NACM. But then NACM provides.

and HCM 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 you know may.

be 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 Afecampton and more of that and why.

and how that may afford a potential advantage and have paths will come over time. Thanks, Matt. Thanks, Carter. Thank you. One moment for our next question. And our next question is from Tessa Romero with JP Morgan. Your line is open.

Yeah, good afternoon, Robert. And, 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 ACI-Campdans emerging profile that may be the most kind of needle moving for the positions in the clinic here? And what are the prescribing factors that are most important for physicians and how much variability is there?

We think BMS is doing a good job with BAVA-Camton 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 AFI-Camton 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 for 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 as he can't and should it get approved. So things like not having to worry about other products that a patient could take around drug.

monitoring and kind of patient follow up. So I think they are coming to be real issues in the marketplace potential. Your differences I should say not issues, but obviously we have to wait till phase three and what our data would very out the shape we can truly differentiate. You know, having a second cardiac mice and 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 AFI-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 AFI-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. Thank you for taking our question.

Just maybe too for me that have been topical for a lot of investors recently. Maybe if you could have a pine in terms of your discussions with a cardiovascular team over at FDA and how explicit they have been in terms of end points for pivotal non-obstructive hypertrophic cardiomyopathy studies.

Your peer, as 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. Thank you.

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 kind of little study. And then a real quick one after that. The enrollment for Sequoia 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 you're on.

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 1 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 your end, thank you.

So I'll answer the second part of your question and then ask Fadi 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 three study of NHCM, I think when we elaborate on that study once it is underway, you'll see some similarities to the ongoing phase three study with Mavicampton, but also some notable distinctions based on AFI Campton has a different profile. But I'll ask Fadi to comment on sort of what's clinically meaningful with regard to some of these endpoints.

Well, I think the endpoints we can use in NHCM in a lot of way mirror what we'll use in OHCM. They're function and they're symptom. They include speak VO2. They include KCCQ. They include NYJ class. Men and 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 and pivotal trials before and.

Obviously, we see the BMS design incorporates that into the 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 of five points or more in the KCCQ that's a little arbitrary. You know, you have to look at the whole distribution and ask, is that driven, you know, 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 others don't.

respond that, you know, 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. 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 NIH and NHM. You know, my hope is that you'll see data in the poster on Sunday that will be revealing.

as to how AFI Camden may be received in NHCM. And again, I'll remind you, we're gonna have a call with investors and analysts Monday morning to walk through those data as they were presented the day before. And that'll inform how we might can elaborate on what would be a phase three study design in connection with duration of treatment and time to endpoints. So, thank you. 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. Hey, Robert. Thanks for taking the question. Just one on the upcoming rel-descendent 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. Yeah, I'm going to ask Stuart, our chief medical officer, to comment, but I'll…

mentioned 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.

mentioned 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 Thank you Jason.

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 design in that way to send to a mask sort of a magnitude of change and ALS FRSR. So essentially it's binary. So either an upsized or not.

With respect to the timeframe for continuing enrollment, I think that's sort of better discussed when if that recommendation comes forward from the Data Monitoring Committee, but enrollment becomes going very well in Courage ALS and we don't expect a major delay in completing enrollment even if the trial's upside.

Maybe just to expand on that a little bit, I'll ask Fadi to comment on how the data monitoring committee is being guided. Yeah, so I think the, you know, the interim analysis uses what's called a promising zone construct, which is either if you have a, it's a construct trying to void what, like term the near myth 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 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 she 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 increments, that would increase the power of the study. And the other scenario is there is a chance of study could stop her 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. 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. Thank you. Thank you. Thank you. One moment for our next question.

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 Rowley and I apologize up front. It is your line again in your question. My lines are mistakes, my line areAlexa Ren title for Murphy Walsh.

over and persistence and has relibrary impact at that. And third, again, going to relibrary, 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 Fadi wants to add on top of that. We're not commenting on the number that 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.

put it into a zip code. Then I'll turn to Stuart, maybe, to answer the other two questions. Thank you for questions. With respect to the open label extension, I think it's, we can say that most of the patients are rolling over it into the extension, so that study is going well.

The impact of delivery O, not surprisingly, there has had some impact in terms of enrollment in North America. We have a large portion of patients, enrolling in Europe , as well as Australia. So it really hasn't had a lethal impact. It's been 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 delivery out to enroll in the trial.

So any approved therapy is permitted as background therapy encourage ALS. That's interesting. Okay. And then the last one in terms of enrollment that is being allowed. Is that what you just said? Yeah. That's right. Yeah, they're allowed to enroll in the study if they're on Relivio. That's by incorporated by amendment. Okay. Okay.

Just similar to we allow patients on Daravone or patients on Rilazole to participate. Yep. Yep. Got it. Thanks for taking the questions. 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 everybody.

Hi, our average 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 Appy Campdenin, OHCM. Just wondering what type of blocking and tackling remains before I'm just showing the study and if it's reasonable to expect.

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 said before. We are packaging and labeling and manufacturing for different supplies of an afficampton, a placebo for afficampton.

sorts of things. And as you mentioned, the FOIA is ongoing in terms of its enrollment and our preference obviously is not competing against ourselves. So there's a bit of load management here that's ongoing and I think we'll see the study start you know.

in these same time frame that we see is choir winding down in terms of enrollment. Great. Thanks, and look forward to the presentation as we have. Thank you. Thank you. One moment for our next question. Our next question is from Saleem Saeed with Miss Eul. Your line is open. Thank you, Saleem. Thanks for the question. I guess one for me and Sequoia.

actually give us the baseline peak VO2 prior to readout so we can handicap the trial. Good questions. I'm going to ask Fadi to answer them.

Well, so, Celine, I think you know probably that we haven't reported it and the protocols for Redwood and Forest don't include exercise testing, peak-to-two testing. So we don't have any data per se with that test and AFI-Campton. You know, 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 p-p-o-2 at 1.4 was...

less than 0.001 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 mice and inhibitor. And so that helps to be risk if you will, the primary endpoint of this trial. Thanks, Vady. Will you guys believe provide the baseline at some point, do you think, or? Yeah.

Probably right before you see the primary outcome. I don't think we'll be providing the baseline characteristics prior to the studies 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 Bellinger with Needham Co. Your line is open. Hey, Serge. Hi, everyone.

Hey, Robert. Good to hear you again this afternoon. Two questions on the Afro-Canton Phase III 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...

the other face retrial in HCM, given that you can have three face retryels running concurrently. And then secondly, in terms of the regulatory strategy, should we expect that both the Maple and the NHCM face retrial to support efforts, FNDAs, once they're there, complete. Thank you. Yes, so I'll answer the second part first. Our registration strategy, the critical path is.

paved with Sequoia HCM and will 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 Omecamp to McCarble, where there is a significant time lag from a US submission to a European one.

In HGM, 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 Fadi to address your first question regarding expected duration of enrollment in those second and third phase three studies. Yeah, I think it's a 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'd like to 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've seen in Sequoia. And I think it's a little too early. I mean, we've enrolled the NHCM cohort in Redwood quite briskly, and I'm optimistic we can do so in a Phase III trial as well.Know that your scoreas were x, y, x, and j with a y with an oliver with a sine omega sine?

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've seen in Sequoia. And I think it's a little too early. I mean, we've 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.

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, how's it going? Thanks for taking our question. I guess kind of following up on Maple HCM, I'm wondering if you have any thoughts on the

I'm going to curious, how should we think about this trial and the potential kind of clinical impact and utility of ACI camp then if this trial successfully? What kind of white space in the obstructive HBM space, keeping this drug, this trial uniquely addresses? And I guess to have studied back 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?

AFTI, 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 talking about what could be the value of demonstrating effects of rather AFTI, Campton, relative to Metoprol, but then Andrew should also comment.

You know, 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, the support, if you will, using Apicamtin 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 symptoms. You don't see really any improvement in exercise capacity. And so how does that compare in a head-to-head study with afecamtin, 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 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

position this mechanism of action and both in their practices but also in their guidelines.

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 the use

guideline adjustments, as well as the way payers think about what steps are required prior to, say, afecanting getting reimbursed. You know, 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 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 AFI Kempton. Great, thanks. And we also look forward to seeing you this weekend. Ben, yay's on me. Thank you. Very good. I'm showing no further questions at this time. I would now like to turn the conference back to Robert Blum for closing.

banded development program for ATHY Campton. Not to say it's not also important for Reld Assemptiv and our early pipeline, but I do think we're aligned with shareholder expectations that ATHY 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 only campdive 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 Athei Campton.

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 abreast of our progress this year. This concludes today's conference call. Thank you for participating. You may now disconnect.