Great. Thanks everyone for joining the next session. It's a pleasure to be here with Cytokinetics. We have Robert Blum, CEO, Sung Lee, CFO, Steve Heitner, the Head of Clinical Research, and Jeff Lotz, the VP of U.S. Sales and Operations. Robert's going to give a quick presentation and then we'll dive into Q& A. Thanks everyone for being here.
Thank you, James. Good morning everyone. Thank you for your interest in Cytokinetics. I'll make a brief presentation before we have a Q& A session, and I'll be updating you on progress at our company. Joanna, next slide please. I'll be making some forward-looking statements. Of course, I refer you to our SEC filings as it relates to risks and caveats to those statements. We do not undertake an obligation to update with regard to those forward-looking statements. Thank you. Next slide, please. Here's our mission, a mission that I hope is familiar to you. We've been at this for a while, executing very effectively towards bringing forward new medicines that we hope may improve the health span of people with devastating cardiovascular as well as neuromuscular diseases rooted in the etiology of impaired muscle function.
Ours is a company both as a pioneer and a leader in translating muscle biology to a new muscle pharmacology. Next slide, please. Here's where we are at this point in time. Our pipeline reflects our commitment to muscle-directed medicines. In particular, as you can see here, those referred to for potential in cardiac diseases. At this presentation today, we'll focus on those specifically that are targeting myosin, the mechanochemical enzyme that is responsible for generating muscle force in cardiac muscle. In particular, today we'll talk about Aficamten. Aficamten is a cardiac myosin inhibitor. It's pending FDA review and potential approval based on a study called SEQUOIA in patients with oHCM, or obstructive hypertrophic cardiomyopathy, a disease of hypercardiac muscle contractility.
Sequoia is a phase III study, a pivotal study that delivered very promising results and hence was the subject of NDA submissions with a PDUFA date at the end of this year. You can see it there, December 26, but also as is pending potential approvals in China and Europe. Aficamten is the subject of other studies, including a study called MAPLE as monotherapy in OHCM and a study called ACACIA. I'll be sharing some results from MAPLE, recently presented at the European Society of Cardiology and again secondary analyses this past weekend at the Heart Failure Society of America meetings. ACACIA is a study in nHCM that is expected to read out in the first half of next year. This is a three-legged stool for Aficamten: SEQUOIA, MAPLE, and ACACIA, with other studies like CDER in pediatrics.
As you can see, it doesn't stop there as we have other myosin modulators, one called Omecamtiv being developed as a potential treatment for heart failure with reduced ejection fraction. Also, (Inaudible), another cardiac myosin inhibitor, is being developed for heart failure with preserved ejection fraction. This forms the cornerstone of our ambitions to develop a specialty cardiology franchise. Next slide please. With that in mind, please understand as we think about our business, we're ruthlessly focused on building what we believe can be an enduring and sustainable business directed to these three drug candidates, focused on a concentrated customer segment treating high unmet need, specialty cardiology indications. You can see here the rapidity and the frequency of expected news flow relating to potential launches associated with these potential medicines. Next slide please. As I mentioned, SEQUOIA was a study that formed the basis for our NDA submission.
More recently, we've had the privilege of sharing with the public data and results from MAPLE-HCM , and here this study, a second phase III study of Aficamten in patients with oHCM , demonstrated very encouraging and promising results. Improvements in the primary endpoint of change from baseline in peak VO2, while the standard of care beta blocker Metoprolol actually demonstrated a decline in that and other endpoints. This is causing a turn of the heads, if you will, in terms of what has been a standard of care in this disease for quite some time. My colleague Steve Heitner will be able to speak to these data here in a moment. Next slide please. There is high expectation and anticipation for the potential pivot and extent of Aficamten to include potential patients with non-obstructive HCM, as is being studied in another pivotal phase III trial called ACACIA.
Enrollment has been completed. Results are expected in the first half of 2026. Patients with n HCM represent the flip side or an equivalent sized population to the patients with o HCM. Hence, you can understand how that represents even more significant promise for Aficamten in the treatment of patients with both o and n HCM. Again, these results are expected first half next year, hopefully shortly after we go to market with a commercial launch that Jeff, our Head of Sales, will be speaking about here in a moment. Next slide please. Here you begin to understand the longer term business strategy, a go- to- market initially in HCM where there are few available therapies, high unmet need, a concentrated customer segment, attractable base for our hopefully producing a high return on investment and sales, and where we believe we'll be in a good position with regard to payers.
That then extends to our similar ambitions, same kinds of investments in commercial activities where that extends to also HFrEF and HFpEF, and we believe we're in a position to do something quite unusual, building a specialty cardiology franchise over the next three to five years. We think that could be quite rewarding for shareholders and all of our stakeholders. Next slide please. From the financial standpoint, we ended June in a strong financial position not only in terms of cash and cash equivalents, approximately at that time $1 billion on the balance sheet, but also with access to additional capital that comes from deals we've done previously, including a deal with Royalty Pharma that afforded us at that point in time an additional $425 million. Our CFO Sung is on the line today.
He'll be able to answer questions about how we're thinking about capital structure, capital efficiencies, access to this additional capital. Also, subsequent to the quarter end, we did a refinancing of a prior convert, an upsized $650 million refinancing. I'll refer you to our 8-K filed on September 22nd , with regard to all of the net proceeds, and Sung is available to answer questions about that deal, further reinforcing a strong financial position as we turn the page on the narrative for our go- to- market activities. Next slide please. Thank you for your interest in our company. We're available now to engage in a Q& A, and James will turn it back to you.
Awesome. Thanks for that, Robert. Very helpful overview. I definitely have a number of questions, so I want to try and get into as many as I can. I think obviously, naturally, a big focus is on Aficamten and the outcome in PDUFA. You had your late cycle review meeting recently where it kind of sounds like it went favorably. You continue to expect a differentiated risk mitigation profile. Maybe it'd be great to understand what you see as the potential scenarios as it relates to the labeling and the REMS here, and exactly sort of how you define, you know, differentiated.
Sure. I'll start and then I'll turn it over to both my colleagues, Steve and Jeff. We have consistently been expecting a differentiated risk mitigation profile as brought about by both labeling and other measures. We do believe that based on interactions with FDA both prior to and NDA submission and more recently during the FDA review, we can consistently lean into that statement. We have studied Aficamten in a way that distinguishes itself in terms of dose titration, echo monitoring, safety, tolerability, and drug-drug interactions.
While I don't think it would be appropriate to go into specific details given ongoing FDA interactions, I will say that the framework that we have studied Aficamten in, in SEQUOIA and in the ongoing FOREST Open- Label study, has led to conversations with FDA that we believe has FDA recognizing its distinct physiochemical and pharmacokinetic profile and enabling flexibility, ease of use, and convenience as would be potentially defining Aficamten if approved. What do I mean by that? I mean that we've gone to great lengths to demonstrate how Aficamten, given a short half-life and rapid reversibility, can be enabling of ease of use and convenience and where if Aficamten may uncommonly be associated with certain EF excursions below 50% and down. Titration seems to have been well- tolerated in clinical study.
We believe that FDA has been permitting of us to continue that practice in the ongoing open- label extension for us with flexibility in terms of dose titration and few echoes as would be monitoring for that. We've also generated data that shows a lack of clinically meaningful drug-drug interactions and we think FDA is recognizing of that too. With our recent refinancing of our convert, we issued an 8-K that spoke to the fact that we recently convened a late cycle meeting. FDA in advance of that meeting provided to us comments both as to label and also as to REMS. We think that based on receipt of those comments from FDA that we should continue to expect differentiation if approved.
With that, I may now turn to both Steve from a clinical standpoint and Jeff from a commercial standpoint to talk about how we foresee differentiation again without being specific about ongoing FDA interactions. Please.
Thanks, Robert. I'll just, I guess, distill a little bit of what you said. You know, we've worked hard in clinical research to leverage the pharmacology of Aficamten, and we've embedded what we believe to be the benefits of Aficamten into our clinical trial design so that you can see, you know, we were able to titrate as early as every two weeks. We showed that it was a successful strategy in both SEQUOIA and in MAPLE. Subsequently, we went back to FDA and modified the protocol of FOREST- HCM. In that protocol, we have flexibility as to when a patient can come back in for their titration echoes, so every two to six or so weeks. In certain situations, in fact, in the vast majority of patients, they're only needed to come in every six months thereafter for monitoring echoes.
I think that we've demonstrated success in all of those metrics, and of course, we're hopeful that FDA will recognize that success and enable us to embed it into our label and monitoring. Jeff.
Yes. I guess I'll just add from a commercial perspective, assuming we're approved and we are differentiated, you know, on all those attributes that Robert and Steve mentioned, we feel that, you know, it'll definitely unlock a larger prescriber base and more patients because we know that there are certain things, you know, in our dosing scheme and monitoring scheme that would be potentially less burdensome to cardiologists and patients than the current CMI . When you pair that with MAPLE, which, you know, the results are specific to Aficamten, that could also further then unlock more patients and prescribers.
Yeah, super helpful color and makes total sense. If we think about, obviously within the REMS itself, there's a lot of angles to kind of differentiate on, you know, MAPLE. Obviously, seems like it'll be a great tailwind for just the whole CMI space, especially for those docs that maybe aren't as intimately familiar with the CMI class or may still have some questions. I guess in the context of all of that, as we look at 2026, what should our sort of expectations be? Should we be, should Afi be getting as many patients going on as Mavacamten? Should Afi kind of track above Mavacamten? What's the right way to think about how all those attributes should translate into the actual lump?
Mavacamten is the first-in-class cardiac myosin inhibitor being commercialized by BMS , and they're doing a very fine job. Currently, there are roughly 15% of what we believe to be diagnosed and treatment-eligible symptomatic patients with oHCM who are getting Mavacamten, and they're doing well by it. It's our expectation that if Aficamten is approved, together we can grow the cardiac myosin inhibitor class to penetrate substantially more. Right now, it's a highly concentrated customer segment that's prescribing, roughly 600- 700 physicians, accounting for over 80% of the Mavacamten prescriptions. As Jeff alluded to, it's incumbent upon us to see if we can get more physicians comfortable prescribing for more patients.
As it relates to preferential share of the category, I think it would be reasonable to assume that our aim is to, with a next-in-class profile, achieve preferential share and be enabling of that to occur hopefully over the first year. Certainly, we expect that BMS will continue to invest in development of market education and awareness, and we intend to join them in that initiative. All in all, I expect this, like other cardiovascular categories, to demonstrate that a next-in-class entrant can be enabling of a lifting of the tide for all boats. Right now, I think BMS should expect north of $1 billion in worldwide sales for Mavacamten in this calendar year. We hope that we'll join them alongside of that in building a meaningful category for patients and for shareholders.
Okay, great, that's helpful. Yeah, preferential share and even, you know, sounds like maybe even within the first year. I think you did a good job or helpful, you know, laying out the color around the REMS and you know, why it can be better. I do want to jump to non-obstructive because there's been a lot of, you know, investor focus there I think post- ESC and that's been an evolving sort of discussion with, you know, Cytokinetics. Yeah, you know, we were surprised at how kind of close ODYSSEY was despite all of its kind of dosing challenges. It would be great to kind of hear your thoughts on the data, how Aficamten's dosing profile and PK may allow for differential dosing, and your expectations for ACACIA now having those data in hand.
Yeah. It is very important that we not make comparative statements Aficamten versus Mavacamten. Certainly, ACACIA was designed in a certain way that we believe could be enabling of a positive outcome in a non-obstructive population. I'll turn it over to Steve, who's the principal architect of that study design and around which we believe, based on information arising from REDWOOD Cohort 4, a phase II study, we continue to be encouraged and optimistic about what ACACIA could demonstrate for us.
Thanks, Robert. I'll start out by building on what Robert just mentioned, which we believe is a potential benefit to how we went about the design of ACACIA. We did a study, REDWOOD Cohort 4, which is an obvious through line between that study and the design of ACACIA. The dosing schedule is the same, the patient population is the same, and our expectations are, in our opinion, more likely to hold true when we take less of a leap of faith between the phase II study and the design of the phase III study. Additionally, we presented some data this weekend at the HFSA , which looked at those patients originating in the REDWOOD study that have proceeded through the FOREST study.
We've shown that those patients actually dose escalate to the highest available doses of 15 mg and 20 mg and tolerate that dose level for up to two years, just under two years. The therapeutic effect on those patients is quite remarkable, with the caveat being that it's a single arm study, but 80% of patients enjoying at least one class improvement in New York Heart Association functional class and 70% reduction in NT-proBNP. We've also shown in our obstructive cohort that the strongest predictor of exercise performance is actually the relative reduction in NT-proBNP. We believe that 70% reads out quite favorably as to what to expect from the ACACIA peak VO2.
We showed that we demonstrated more than a 10-point improvement in KCCQ, which is what our expectation is and what the study was powered on, with a delta KCCQ of more than five points between the active and the placebo arms in ACACIA. I think that we have substantial clinical data from phase II and the long-term extension which support the positive phase III study of ACACIA.
Yeah, yeah. Those data this past weekend were interesting for sure. On that point on KCCQ, obviously, I think maybe one of the things that jumped out to us in the ODYSSEY data was the placebo response was quite high, much higher than we see it in obstructive versus BMS' phase II and non-obstructive. Like what do you think drove that? You know, what is sort of your expectation for placebo in ACACIA ?
Robert, do you want me to take that?
Please.
I guess the overarching answer to that question is we don't know. We can speculate as much as the next person. I will say that you've already kind of pointed to this being an outlier, and that's the nature of statistics. It could very well just be plain old bad luck that the placebo group did demonstrate a greater than expected placebo effect. I think that's probably the safest bet. There are other speculative answers to that, but I don't necessarily want to go into those at this point.
Yeah, fair enough. It definitely seems like an outlier. Okay, great. In terms of, you know, at the end of this weekend the LVEF less than 50% rate was, you know, encouraging. It remains low over, you know, two-week, two-year period. How much can you track on like a blinded basis in ACACIA on this ejection fraction drop rate, and is there anything you can tell if it looks different than what you see in obstructive?
Robert, do you want me to take that again?
Yes, please.
I'll start out by saying the BMS development program have focused on the cutoff ejection fraction below 50% as being a safety measure. We only had one patient in FOREST-HCM have an EF of under 50% during a two- year period, which kind of translates to a very low exposure adjusted event rate. Now your question is, what do we know from ACACIA? We don't, obviously it's a blinded study so we don't know the absolute ejection fractions of any of the patients. What we do know is that if a patient drops their ejection fraction below 40%, we are notified. Now I'm not going to give you specifics on that, but we are notified in that situation. Other than that, we're totally blind to ejection fraction.
Suffice it to say that the open-label extension now, as you've seen data out to 96 weeks, is perhaps the best indicator of what we might expect from ACACIA. For the fact that you already know that we're getting patients up to the higher doses in FOREST and we have such a low experience with EF below 50%, I think that augurs well for what we should expect from ACACIA.
Yeah, makes sense. I know we're a minute over, I just want to ask one last question. There's a million more I could ask, just to kind of close the loop on ACACIA. Obviously you added pVO2 to the co-primary. I know you're splitting the alpha kind of across both. What exactly is like a win for regulators? Is it just one of those hitting below 0.025? Do you need to hit both? Does it vary kind of across geographies? Just real quick, any color you can provide there.
I'll take that, Steve. I think our expectation is that the study is positive if one of those is statistically significant. FDA is certainly not going to be focused solely on that. FDA will want to appreciate that we're seeing positive trends in both and that hopefully they're both statistically significant. At the end of the day, I think that will be a matter of conversation if one is and one is not. It wouldn't be, I think, advisable for us to pursue an approval if one is positive and the other is negative. Instead, I hope that we'll see that both are demonstrating favorable benefit for patients.
Okay. Okay. Sounds good. Makes sense. It seems like, I mean, even in ODYSSEY, it didn't work, but it seems like we've seen the two track pretty well kind of over time.
I'll also say that, you know, don't sleep on the fact that we've had continuity of team in the design and conduct of these studies. Steve himself, having treated many of these patients, now in house designing these studies, I think keeping to the same dosing regimen, going back to centers that we know quite well, and being in a good position to oversee the conduct of a study like ACACIA, confers some advantage to us as we hopefully have designed and are executing on a very proper phase III trial.
Yeah. Yep. Definitely makes sense. Something that comes up with our doc discussions is the importance of that in a disease like non-obstructive, and, you know, how obviously you guys have executed very well in HCM trials. Makes total sense. Awesome. I know we're up on time. There's a lot more questions I could ask. I appreciate you guys all taking the time to join, and thanks, everyone, for listening in.
Thank you.