Good afternoon. Welcome to Needham's 23rd annual healthcare conference. I'm Serge Belanger, one of the Healthcare Analysts at Needham. For next session, we're happy to have Cytokinetics. We have the company's CEO, Robert Blum, who will give us an overview of the company, and then we'll move on to some Q&A. For those listening online, you do have the option to submit questions via the portal you're watching the presentation on. We'll be asking those questions as they come in. So I'll hand it over to Robert to give us an overview.
Thank you, Serge, and thank you to Needham for inviting us again to provide an update on Cytokinetics' recent progress and prospects. I'll be making some forward-looking statements. I'll refer you to our SEC filings for caveats to those statements, and we don't undertake any obligation to update those statements, but refer you instead to those factors described in more detail in the filings. As hopefully you've come to know us, we're executing on a mission and a vision to bring forward new medicines with focus to muscle biology to improve health span of people with devastating cardiovascular and neuromuscular disease, all of which are associated with muscle dysfunction and weakness. We're well into advancing a pipeline that is all organic to our drug discovery and development.
At Cytokinetics, we've been focused to primarily those, activators or inhibitors of proteins involved in sarcomere mechanics and biomachinery, and in particular, as read on our ambitions to build a specialty cardiology franchise anchored by aficamten, which is our next-in-class cardiac myosin inhibitor. Here on this slide, you see that we're developing it for obstructive and non-obstructive hypertrophic cardiomyopathy, a disease of cardiovascular severity associated with hypercontractility, where the therapeutic goal is to suppress that. As you may know, we toplined results from SEQUOIA-HCM, a pivotal phase III study of aficamten in patients with oHCM, and we're conducting ongoing phase III studies, MAPLE-HCM and ACACIA-HCM, in oHCM and nHCM, respectively.
But we're also advancing CK-586, another cardiac myosin inhibitor, this year from phase I to phase II in patients with heart failure and preserved ejection fraction, while also continued interest with omecamtiv mecarbil, our first-in-class cardiac myosin activator for patients with heart failure and reduced ejection fraction. So these myosin-directed therapies are the cornerstone of our pipeline anchored by aficamten with other specialty cardiology and muscle biology programs underneath the hood, so to speak. As we're building out our specialty cardiovascular franchise anchored by aficamten, we're looking at diseases of severe cardiovascular impairment.
Here you can see on this slide how each of these drug candidates directed to the same cohesive biology address populations that are sizable and where there's high unmet need, and where a muscle-directed strategy, we believe, builds substantial and enduring value for translation of this science to potential medicines for patients and for reward for shareholders.
As we advance, you'll see that SEQUOIA-HCM, which, again was toplined in December by press release and will be the subject of presentations and publications in this second quarter, in particular in May, you'll see here that we've already indicated that SEQUOIA-HCM met its primary endpoint and all 10 pre-specified secondary endpoints, highly clinically meaningful and statistically significant effects, including, large differences, placebo versus active, on the primary endpoint of change in Peak VO2, as well as other improvements in symptoms and effects, functionally, accompanied by, we believe, good safety and well-tolerated profile, and in particular a low incidence of ejection fraction excursions, which thereby play into our strategy for next-in-class positioning, as we'll be able to elaborate more with presentations and publications in this second quarter.
As we think about building uncommon value for shareholders, we produce this slide, which elaborates on all of the very important milestones that we believe will be unlocking of shareholder value this year, next year, and the following years, as Cytokinetics is already in that rarefied air of market cap range, but for which we believe we can substantially increase shareholder value even more by advancing this science, this biology, and in particular in these specialty cardiovascular indications adjacent one to another, as would be in, establishing enduring value for our commercial business and shareholders. We think we're uniquely positioned for success, as elaborated on this slide. We are both the pioneer and the leader in this area of muscle biology. We're very focused and disciplined to where it has relevance to specialty cardiology. Over 25 years now, we've established key relationships with the most meaningful stakeholders.
That includes opinion leaders in the physician community, but also in the payer community, as we believe that we've also demonstrated that we can be prudent in terms of access and diversification of capital and efficient in terms of how it's deployed, preserving value for shareholders and all stakeholders. As we reported with our Q4 earnings call recently in February, we believe we have a strong balance sheet reflecting in terms of current cash and that which is obligated by Cytokinetics to pull down from our deal with Royalty Pharma, over two years of current cash in light of the guidance we provided for this calendar year. We have other deals that we're pursuing that we hope will not only add to the balance sheet, but further extend our cash runway this year.
Here are the important milestones for the company, as laid out with our guidance in our Q4 earnings call. Foremost amongst these is the presentation and the publication of results from SEQUOIA, the submission of an NDA, a rolling NDA in Q3, and also an MAA to EMA in Q4 to support our go-to-market activities next year, continuing the conduct of MAPLE and ACACIA and the further advancement of our pipeline as we build both a commercial business built around this biology, but also augment further our research and development pipeline to provide sustainable value for the company and its shareholders. With that, Serge, I'll turn it over to you. Thank you for permitting us to provide these introductory comments.
Great. Well, thanks for that overview. I know we're going to speak about SEQUOIA, but before we move to that subject, you did present some new data at the American College of Cardiology meeting over this past weekend. It's additional data from the FOREST extension study. Maybe just highlight what that data was and how it supports the overall program.
Yeah. So this weekend at the American College of Cardiology, we presented a poster from FOREST-HCM. This is the open-label extension study in which patients from our phase II study, REDWOOD-HCM, as well as patients from SEQUOIA-HCM, the phase III study, are enrolling. And here we presented an update in FOREST-HCM, which included patients at 48 weeks. These data comprised an update to that which we presented last year. 213 patients are now in FOREST-HCM as of this data cutoff, and 46 of those patients had completed 48 weeks of follow-up at the time of the current interim analysis.
The data we believe are quite strong, reinforcing a next-in-class profile, sustained reductions in left ventricular outflow tract gradients, sustained improvements in New York Heart Association functional class, where 82% of patients improved by greater than or equal to one New York Heart Association class with no instances of worsening. We also saw significant reductions in NT-proBNP, a biomarker of cardiac wall stress, a decrease of 63%, which is a large decrease at week 48. We also saw that treatments with aficamten resulted in statistically significant improvements in measures of cardiac structure and functioning, as well as, these patients who came in, 19 of the 46 who were at that time at baseline meeting guideline eligibility for septal reduction therapy, surgical intervention at 48 weeks, only one of those patients still remained eligible for septal reduction therapy after six months of treatment. So that's a 94% reduction.
All this was accompanied with a well-tolerated profile, only a modest reduction in LVEF, left ventricular ejection fraction. Those three patients who saw EF below 50%, two of them asymptomatic, and one downtitration occurred, due to recurrent alcohol-induced AFib. These data we think reinforce the efficacy and safety of longer-term treatment with aficamten, as we believe is supportive of potential approval and our positioning, as we expect, hopefully, a differentiated profile in the marketplace inclusive of a differentiated REMS program to mitigate safety risk.
You mentioned there's now 213 patients enrolled in FOREST. So those are all from REDWOOD as well as some from SEQUOIA?
Yeah, most of those patients are coming from REDWOOD. And as SEQUOIA completed and patients then enrolled, there are certainly large numbers of patients in FOREST from SEQUOIA, but not so many yet at the 48-week time point.
Okay. And it sounds like they enter the study at the 15-mg or 20-mg dose and remain on those dosages for.
Actually, they start the dose titration all over again, but most of them titrate up to 15-mg or 20-mg.
Got it. Okay. And then let's talk about the SEQUOIA dataset. You've now had it in your hands since late December. I know you wanted to present it at the ACC meeting this weekend, but it wasn't part of the presentations. Just curious if it was still part of discussions.
You know, from what I'm hearing from my colleagues who attended the meeting, SEQUOIA was very top of mind for the attendees at the American College of Cardiology. You know, we knowingly in disclosing more in our topline press release in December were violating the embargo policy of the American College of Cardiology. We frankly had no choice because in order to meet those expectations of material disclosure, that which we thought was material to shareholders, we needed to disclose more than ACC would be permitting. We did so. In that way, we lost the opportunity to present at the ACC. These results will be presented in mid-May at the European Heart Failure Meeting. It'll just be another month before you'll see them in their full glory, both presented and we believe published concurrently.
You'll hear from us soon regarding the presentations we expect to have there in mid-May. What I'll share with you is while we've provided a lot of information in the top-line press release, we believe these results get better and better with these additional analyses and presentations and publications. We'll lay that out in full glory, starting in May, but with other presentations and publications throughout the year.
Okay. So maybe just highlight topline, you know, what was most impressive about the dataset. And since it hasn't been published and presented yet, I don't know how many, you know, how much KOL feedback you've gotten, but if you can share any of that, even if limited.
Yeah, we've gotten lots of KOL feedback. And, you know, this study was designed and conducted by KOLs in that we hired, to work at Cytokinetics several years ago, the leading HCM academic specialists who were the lead investigators for the first-in-class drug candidate, called mavacamten. They came in-house and helped us design and oversaw the conduct of SEQUOIA-HCM. So they, in speaking with their peers on the steering committee and the executive committee of this trial, have gotten lots of feedback and where I think there's a very high level of enthusiasm for the SEQUOIA-HCM results affirming of our next-in-class profile. And our goal here is to, with aficamten, expand the number of physicians who feel comfortable prescribing a cardiac myosin inhibitor for a broad array of patients. Only 3%-4% of eligible patients we believe currently receiving a cardiac myosin inhibitor.
So the results of SEQUOIA that are most impressive include the large magnitude change in peak VO2 measured by CPET at week 24, where over standard of care, there's a quite significant increase in exercise capacity, accompanied by improved measures of KCCQ and improvements in NYHA at week 12 and 24, and where that's demonstrating the effects of aficamten are occurring early in the treatment upon dose titration and being maintained at weeks 12 and 24. So we're very encouraged by that, and especially as is accompanied by no heterogeneity in treatment effect, no evidence of subgroup heterogeneity, no attenuation of effect in patients treated with beta blockers. So with or without beta blockers, we're seeing these large magnitude of effect.
And that augurs well, we think, for the MAPLE study, which is looking at aficamten head-to-head with metoprolol, which is due to complete enrollment this year and readout next year, hopefully concurrent with our FDA and EMA approvals and commercial launches. So we believe that the SEQUOIA data, when they are presented and published, will be reaffirming of the enthusiasm that was evident with the topline press release. And you'll see these data now, in their full glory.
Should we expect to see additional subgroup analyses and deeper dives on the safety tolerability side?
Yes, indeed. You'll see that. And also, how that reads, we believe, on real-world practice of using cardiac myosin inhibitors, in this case in particular, aficamten, for the benefit of patients. So you should expect to see several presentations that elaborate on these data, not just that which was contained in the topline press release.
Okay. And maybe while we're on the subject of safety tolerability, if you can just talk on how that could impact the potential REMS program. That seems to be the new discussion focus. As you mentioned before, there, between SEQUOIA and the FOREST dataset, there's a low number of ejection fraction excursions. But yeah, how do you think that impacts a potential REMS program and how you're thinking about it?
Sure. So aficamten was designed to have a short half-life and a flat PK/PD relationship enabling, we believe, of dose titration convenience, rapid onset, rapid offset, and therefore be physician and patient-friendly. That was borne out, we believe, in the SEQUOIA results. And, you know, FDA was permitting of us, if ejection fractions fall below 50, to simply downtitrate and not dose terminate. And that strategy seemed to work very successfully in SEQUOIA, and as is continuing in FOREST. We've had a very low incidence of EFs below 50 where the downtitration seems to be all that's necessary. The clinical consequence of that is quite benign. There have been no treatment interruptions for low LVEF and no associated coincident heart failure AEs.
So we think this augurs very well for how FDA will see these results, and this is enabling of our base case assumption that aficamten should be potentially approved with a differentiated REMS, if not arguably no REMS. And we've had consultants suggest to us that a no-REMS scenario is quite possible, but for which that's not our base case assumption. Our base case assumption, the more probabilistic assumption, is a differentiated and lesser REMS.
Okay. When you mean a lesser REMS, you're comparing to the mavacamten REMS?
Yeah, I'm not going to speak specifically about mavacamten and its profile other than to say aficamten is next-in-class. And here we expect labeling that could be differentiated.
Okay. And in those REMS programs, what do you see as the most burdensome? Is it the echo requirements on that kind of is associated with the titration phase, or is it the maintenance echoes?
You know, what we hear from market research, what we've seen, published by equity research analysts that do their own independent work, is that, the adoption of this category has been affected and maybe limited by the frequency of echoes required, both in the uptitration phase as well as the maintenance phase, and the FDA-imposed windows on those such that, if they're not performed within a certain time frame, then one needs to dose terminate or start all over, dose interrupt and uptitrate again. And there appears to be capacity constraints with the number of echoes such that many clinics have to have certain days in order to be permitting of the volume of echoes required, and that limits adoption.
Our hope is that with aficamten, the data from SEQUOIA, as well as the data from FOREST, will lend evidence to the fact that less frequent echo monitoring, wider windows may be permitted in order to be able to provide comfort for risk mitigation without as many or as tight an echo parameter. That's obviously to be determined by FDA upon review of our NDA submission. But our expectation is we're going to be submitting with a differentiated REMS recommendation.
Okay. And I think you've already had some discussions with the agency regarding the REMS and what it could look like. Do you expect to have any additional color that you'll be able to share with us and investors regarding that process?
Indeed. So we've already had two meetings with FDA, both in February. One, a topline meeting to review the results of SEQUOIA. The other, a pre-NDA meeting to ask some questions specific to the NDA process. And in both of those meetings, the subject of REMS came up, and we were comforted and reassured that FDA is going to look at this on its own merits based on data from SEQUOIA and FOREST as could be permitting of a differentiated REMS. Because we have breakthrough designation, we also are afforded other opportunities to interact with FDA. And we've recently requested a meeting, and we've been acknowledged by FDA such that another meeting will be occurring in this second quarter to permit us to ask questions specific to a potential REMS program. That meeting will be occurring in the second quarter.
We'll be able to update shareholders on a quarterly basis regarding these interactions with our earnings calls. We're not going to provide play-by-play feedback with every interaction. But I do believe that we'll be able to provide some general guidance. To be clear, however, once the NDA is submitted in Q3, there won't be anything truly committal from FDA until, presumably, they've conducted a mid-cycle review, and we're in the process, hopefully, of negotiating labeling for potential approval. That won't occur until sometime, we hope, in the first half of 2025. All of this is more informative of our strategy as we'll enable submission of an NDA. But none of this is, I would say, as would be definitive until potentially next year.
Okay. So it sounds like you'll have a pretty good idea of how the FDA is thinking about a REMS. By the time you submit or complete the BLA filing, you won't necessarily have to wait until final labeling decisions sometime.
Well, we'll have indications of FDA's viewpoints based on our submitting of questions and their responding to those questions prior to our NDA submission. And that'll inform our submission strategy. But we won't have anything definitive from FDA, of course.
Yeah. Okay. And in terms of the filing strategy, I think the last quarterly update you talked about, rolling submission was ongoing, targeted for sometime, targeted for completion sometime in the second half of the year.
Yeah, FDA was amenable to our proposal to be permitting of a rolling submission, which we expect to be starting and stopping during Q3. So we'll have it all done in Q3. That could be permitting of them to start a review sooner. But of course, it's not on file until the last documents are submitted, and then they have up to 60 days. So we don't expect it to be on file until sometime in Q4, but maybe the review can begin sooner. And we don't know if we're going to get standard or priority review. We won't know that until Q4. Our base case is standard review, but it's possible we could get priority review.
Okay. You've talked about the role of the MAPLE study in the sense that it would be label enhancing. So maybe just talk about what the initial label could look like and how the MAPLE study could, can modify that.
Yeah. So the initial label we expect would be an approval related to the SEQUOIA results, where a majority of patients in SEQUOIA were on background therapy of beta blockers or calcium channel blockers or both. The good news is, again, we did not see an attenuation of effect in patients with or without beta blockers. But the true test of potential superiority relative to beta blockers will come with results from MAPLE as well as FOREST, where physicians seem to be increasingly comfortable taking patients off of beta blockers. For, I'm sorry, MAPLE. MAPLE is designed to look at head-to-head aficamten versus metoprolol.
There we think, in some ways, the deck may be stacked in our favor based on what we already know from SEQUOIA and FOREST, but also based on what's been published, that beta blockers don't really seem to contribute to increased exercise capacity in patients with obstructive HCM. We think that's key and indicative of impairment of patient function and quality of life. We do think that having MAPLE read out positively could be quite enabling to aficamten potentially moving up in guidelines, into first-line treatment for patients with oHCM. That matters very substantially to payors, as our market research has confirmed, both in the U.S. and HTAs in Europe. We do believe having these data presented and published around the time we go to market, hopefully in 2025, will be very enabling.
Ultimately, it could also be factoring into a supplemental NDA submission and an expansion of labeling potentially in 2026. So that's the MAPLE-HCM study. And we also have another phase III study of aficamten ongoing in nHCM. That's called ACACIA-HCM.
Okay. And that one's started a little later. So if MAPLE is expected to complete enrollment this year and read out next year, the other one is six months or so behind. Is that how to think about it?
At least, you know, we'll have updates on enrollment in ACACIA this year. It's a much larger study, and it's a longer study. Therefore, we're assuming it's going to complete enrollment in 2026. I'm sorry, 2025 and read out in 2026. But that's still to be determined based on enrollment as we roll through 2024. We're pretty encouraged by what we've already seen. Our phase II study called REDWOOD had four cohorts. The first three were an oHCM. The fourth one was an nHCM. There we saw very striking improvements in those same endpoints that we're measuring in phase III. The data from REDWOOD cohort four, we believe, read positively on what we should expect in ACACIA HCM. There we saw striking changes from baseline in cardiac biomarkers. We saw improvements in angina frequency or reductions in angina frequency, I should say.
We saw significant increases in the KCCQ at week 10 and improvements in NYHA functional class. And the adverse effect profile, safety and tolerability, we thought were also very encouraging. So the fact that we're seeking to reproduce that now in phase III in ACACIA hopefully lends support for optimism that ACACIA should also read out positively for aficamten and enable further label expansion, based on those results. So you begin to see how this strategy, SEQUOIA, MAPLE, ACACIA, read on our build of a specialty cardiology franchise, as we hope will be augmenting of shareholder value just in these next couple of years.
Beyond those ongoing studies, any other plans at this point for additional ones that could further expand your label?
So that's it for aficamten, at least as we've considered it so far. I expect there would be potentially some other phase IV studies, and investigator-initiated studies upon approval. But what we haven't yet spoken about is our other cardiac myosin inhibitor, CK-586, similar mechanism of action to aficamten, but differentiated, different intellectual profile. And here we're studying that currently in phase I. You'll see those data this year moving to phase II this year in patients with heart failure and preserved ejection fraction. And this is a population, at least the way we're thinking about it, that's quite adjacent and similar in many ways to patients with nHCM. So it stands to reason as we continue this through line that a mechanism of action of cardiac myosin inhibition may read through positively in these patients.
This is a subset of the roughly 2-3 million patients in the United States with heart failure and preserved ejection fraction. We're less focused to where you currently see SGLT2 inhibitors and other drugs, like the GLP-1s and others showing promise in HFpEF. Those tend to be the more cardiometabolic HFpEF patients. We're going to be more focused on those who have the anatomy more similar to nHCM, where these are patients who have thickened, cardiac wall anatomy, high BNPs, and the objective is to reduce BNP and demonstrate improvements in symptoms and function, as well as potentially outcomes down the road. So we'll start a phase two study with CK-586 and HFpEF later this year.
That should hopefully read out over the next year or so in such a way that we could further unlock value for this biology and for the promise of science delivering to patients who have these additional severe limitations and unmet need.
I think in your slides, you highlighted the large size patient populations and market opportunities in nHCM. Maybe if you can just spend some time talking about your go-to-market strategy, I guess first in oHCM and then how it expands beyond that.
Yes, it's very important to underscore that the way Cytokinetics is expecting to go to market in both North America and also eventually Europe is predicated on a specialty cardiology franchise strategy, distinguished from most cardiovascular go-to-market strategies that tend to be more directed to larger customer segments, more diffuse market opportunities. Here we're focused to severe cardiovascular need largely treated by a relative few cardiologists in concentrated customer segments, including centers of excellence, where a limited investment in sales and marketing infrastructure should hopefully support a high return on investment and shareholder equity. There are roughly 400 physicians currently who represent a majority of the prescribers of cardiac myosin inhibitor and, maybe 50 centers-100 centers of excellence. So we already have in place a large medical affairs, group, payer access, market access group. And I say large, I mean dozens, not more than that.
They're focused to these areas where we can pre-approval be engaging with these centers from a medical clinical standpoint. Eventually we expect to hire, let's say approximately 100 sales reps-150 sales reps that would be upon signals from FDA that we're going to market with an approval. They would be hired in 2025 to support commercial launch in the second half of 2025. We have conducted a good deal of market research, preference share and otherwise, pricing, distribution. We believe that our strategy as relates to a high-touch experience for patients, communicating well with physicians, differentiated labeling, positioning, and REMS should be enabling of us, we hope, to go from next in class to potentially best in class. That's our goal starting next year.
Okay. I think we only have a few minutes left. I got to ask the uncomfortable question. M&A rumors have been rampant even before the SEQUOIA data, especially in the early part of January. Anything you can or want to comment on that front? I know the last quarterly update, I think you mentioned you were not running a sales process. I don't know if you can elaborate on any of that.
Yeah. To be clear, we did not and are not conducting a sale process, but we're very active in engaging with large multinational companies around business development with our focus to partnering aficamten in Japan, where we don't currently have ambition ourselves, nor are we in a good place where we could execute on strategy the way we would ideally want to. So in the course of those conversations, we've met with lots of companies and shared information that's been enabling of us to have advanced discussions. Our goal is to partner aficamten in Japan. And we acknowledge that sometimes those conversations can roll into something larger. We have high expectations for shareholders as it relates to aficamten and our pipeline, but we'll always do the right thing as fiduciaries to ensure we're objectively considering the best way to maximize shareholder value.
I expect M&A will always be a constant for Cytokinetics, always be something in front of us, and we'll have to always do right by shareholders in context of those conversations. But we'll control that which we can control. Right now that means executing as best we can on these clinical studies, this NDA and MAA submission strategy, and our go-to-market strategies for so long as it makes sense that that's in the interest of a go-it-alone. We'll look forward to keeping folks updated on those conversations as they may materialize into other things.
Okay. Well, I think we're up on time, so we'll wrap it up there. Hopefully this is not my last fireside chat with Cytokinetics, and we'll be, we'll see you again next year.
Well, we appreciate always having the opportunity to update here at the conference. We welcome folks who want to meet with us one-on-one. We think this is a very, very exciting opportunity and time for our company after many years of focusing to research and development to be thinking about being in a place where we can fulfill the promise of our science for the benefit of patients and reward shareholders in ever-increasing meaningful ways. Look forward to providing further updates along the lines of those milestones and presentations and publications.
Great. Well, thank you for spending time with us this afternoon.
Thank you.