Great. Welcome everyone to the next session. I'm excited to be here with the Cytokinetics team. Obviously, a super, super interesting and topical time for you guys. Thanks for being here. We have Robert Blum, CEO; Fady Malik, Head of VP and of R&D; and then CFO, Sung Lee. Robert's going to go through a couple of quick slides, and then we'll jump into Q&A.
Thank you. Thanks very much to the organizers for having us here attending. I'll be brief. I'll provide some contextual slides that I'm sure we'll get into in more conversation. I'll be making some forward-looking statements. I'll point you to our SEC filings for caveats to those statements. Of course, we don't undertake obligation to update the forward-looking statements. What I will be talking about today is our company, our company that's been on a mission, a mission for over 25 years to bring forward new medicines rooted in muscle biology that read on health span of people with devastating cardiovascular and neuromuscular diseases of impaired cardiac and neuromuscular skeletal function. Here's our pipeline I'll be highlighting today, in particular one of these drug candidates, aficamten.
For context, you'll see that we have three cardiac myosin modulators that form the cornerstone of our later stage pipeline, other drugs and drug candidates that are in earlier stages of development and research. Aficamten is itself a pipeline in a pill. It's already been the subject of two positive phase III studies, as well as a very extensive open label extension, Sequoia and Maple and Forest, respectively, with another clinical trial called Acacia that's due to read out. That speaks to our continued commitment to science and evidence-based generation, in particular bringing forward life cycle studies into earlier stages, and where we believe Aficamten, if approved by the U.S. FDA later this year, could be enabling of an enduring business. Aficamten is not just under review with the U.S. FDA, but also in parallel reviews in China and in Europe.
As you get to know Cytokinetics, we're in a good position, we think, to launch across all three geographies in relatively short order and build a business off of Aficamten, starting in OHCM and potentially in NHCM, as we think could be very valuable for science, medicine, patients, and shareholders. That speaks to the specialty cardiology franchise strategy that we have here. Today, I'll be talking primarily about Aficamten in HCM and mostly in OHCM, obstructive HCM. You can see how this is continuing alongside other dimensions in heart failure. These are not small markets. They are, in the case of HCM, orphan designated, but we're talking about markets measured in hundreds of thousands of patients and where they are treated by concentrated specialty cardiologists, where we think we can build a reputation, a credibility, integrity, and that can have lasting value.
As you get to know us, you'll also see that we believe this contributes to successive news flow for shareholders and the street launches across these different indications, these different products, and over these years depicted. Specialty cardiology has potential for high ROI, and you can see the attributes here. I won't go into each of these boxes, but I think as you can read, this is borrowing a page from the playbook of specialty pharma, but has applied uniquely to specialty cardiology, as we have for a long time been building evidence to support our business ambitions. Again, I think this offers shareholders high return on investment, high return on shareholder equity. Starting with Aficamten again, and to underscore, we're going to go to market in a way that should make an impact, starting in the United States, hopefully with approval before the end of the year.
Also in Europe, early next year, we recently mentioned on our earnings call, we think we're executing closer to our best case scenario, as could be enabling of launch in Germany first half of next year, with other countries to follow. Our partner, Sanofi, is on timeline, we think, for approval in China before the end of this year. Japan, as partner with Bayer, will come next. We expect to, in accordance with our Vision 2030, be executing on plans to bring Aficamten to patients worldwide promptly. Aficamten is buoyed by very strong clinical data. You can see here very large, meaningful improvements in exercise capacity, as were demonstrated in Sequoia, the pivotal clinical trial to support the initial registration in OHCM.
These data got a standing ovation when presented at the cardiology meeting in Europe and simultaneously published in the New England Journal of Medicine, and represent meaningfully large clinically relevant improvements in an endpoint that matters, as was accompanied by other endpoints in that same study across all pre-specified secondary endpoints. These are data from the second phase III study that were recently presented, also in Europe and also in parallel publication, New England Journal of Medicine. This is what I mean by accelerating life cycle management. We saw here, when compared with metoprolol, first line therapy currently in OHCM, not only does that standard of care show decrement in terms of exercise capacity and other measures, including biomarkers, but aficamten superiority.
When we go to market in OHCM, we expect these data to contribute not just a halo effect, but a catalyst and momentum driver for what could be earlier adoption of Aficamten into first line therapy sooner. These data will not be in the initial label, but we will be in a position where our medical affairs colleagues and our commercial colleagues, consistent with label, can speak to these data, and as would be, we believe, ultimately approved with expanded label in 2026. Acacia is the next phase III study to read out, and we're optimistic about results from Acacia based on open label extension data and phase 2 data, where the same dosing regimen is now being amplified in a larger scale phase III study, and where we're going to the same study centers.
We'll have some things, I'm sure, to talk about during the Q&A about Acacia and its potential. NHCM represents a prevalence and a market size at least as large and growing faster than OHCM. We expect these data from Acacia in Q2 2026, so shortly after launch, and as we think is top of mind for shareholders, especially because a recent study showed a CMI developed by BMS didn't meet its endpoint in a phase III study, but for reasons that are still encouraging and illuminating why we can be optimistic for Aficamten and in Acacia. With regard to our other resources, as Sung can elaborate when we get into the Q&A, we're in a strong financial position. We reported on our Q3 financials last week. We expect to end the year with over $1 billion in cash and cash equivalents.
We have access to additional capital where we want to draw on it from what we consider to be competitive cost of capital loan terms from Royalty Pharma. As we go into our potential launch year in 2026, we think we've also been good stewards of shareholder capital by putting a lid on spending and being prudent with regard to investments. As we hopefully will be in a good position to allow sales revenue and other cash flows to be enabling of sustainable financials for the company. We think we've been prudent in the way we've accessed capital and also deployed capital efficiently. We can get into that with Sung. Here's the guidance that we recently narrowed with regard to 2025.
I think this means that we should end the year in a strong financial position as we turn the corner and hopefully deliver on the next stage for Cytokinetics as a commercial enterprise. With that as context, I'm sure we'll get into some details with regard to Q&A. I appreciate your interest in Cytokinetics.
Great. Thanks, Robert. Yeah, obviously a lot going on and super exciting time for Aficamten. I guess just quickly ahead of the PDUFA, if there's anything you can share, kind of like what's left to get ironed out. Obviously there's been a lot going on at the FDA. Just curious your overall perspectives and confidence as we kind of approach that PDUFA date.
We get a lot of questions about whether changes at FDA and also uncertainties at FDA may be affecting us, not to our knowledge. To repeat, this is a drug candidate that's shown unequivocal efficacy, even relative to a standard of care. We have large, well-controlled clinical trials that met on primary and secondary endpoints with very high statistical significance. We do believe that we're on track with regard to communications and interactions with FDA. We've had GCP inspections, no observations. We have had multiple interactions with FDA, including mid and late cycle review meetings, and those have gone well. We've updated with our earnings calls what's been going on there. We are in possession of feedback from FDA on draft label, as well as draft REMS.
We've had interactions with FDA as to both, and we believe we're nicely aligned in terms of how we should be approaching those matters towards finalization. Even despite questions around what's going on at FDA, we don't foresee how that has in any way affected us or should as we go forward towards our PDUFA date.
Yep, makes sense. Okay. I guess, obviously there's a lot of investor focus still on the REMS, and I think a lot kind of focused on the cadence of maintenance echoes and trying to compare to Camzyos's. There's a lot to Camzyos's REMS? I'd be curious if you could kind of highlight from your perspectives where you think, one, what's most meaningful to kind of differentiate on, and two, how Aficamten's profile will enable sort of differentiation and easier REMS overall.
I'll be careful not to be specific because we are in ongoing discussions with FDA, but I will emphasize that as we've been saying even before we submitted the NDA and when FDA indicated it would be deemed reasonable to submit without a REMS, that even as we do expect a REMS now, we continue to believe that we should be, if approved, Aficamten should be accompanied by a differentiated risk mitigation profile as reflected in label and REMS. We believe both label and REMS will be reflective of the way we've studied Aficamten, where we've built clinical evidence to support the differentiation. With that in mind, maybe I'll ask Fady to speak to sort of how in clinical studies, preclinical studies as well, Aficamten was designed and is demonstrating ways that we think should be differentiated if approved.
Yeah, from the very beginning, we anticipated that this is a mechanism of action that requires careful titration against the patient's underlying severity of their disease. Patients with less severe disease are going to require lower doses, more severe disease likely require higher doses. You want a certain predictability of titration, and engineering that preclinically means a shallow exposure response relationship so that as you increase dose, the treatment effect does not come on like a knife's edge. Translating that into the clinic, again, we saw with titration, predictable improvements in gradients and really modest changes in ejection fraction, no drops in ejection fraction below 40%, a few below 50% that require down titration. When you think about how that might ultimately be translated into a label, it is essentially how we have conducted our clinical studies.
Dose escalation, every echo can result in a dose increase if necessary. Patients do not have to interrupt treatment. If they overshoot, they can down titrate. There is greater flexibility in terms of going from Sequoia to Forest as we have engineered in terms of how dosing windows can be applied. In Forest, we have a dose increase and then a follow-up in a two- to six-week window. Patients likely are to get to 75% of them will get to their target dose within the first three visits and then can go on to maintenance from there.
Yep, yep, that makes sense. I think that is something that resonates with Docs, is the flexibility versus Camzyos is like a little bit more of like a rigid sort of formula.
I guess as you look at the market in the, obviously it's still relatively concentrated in who's prescribing a CMI, is it really the titration that you think is sort of like the biggest headwind to more docs using these drugs and docs using these drugs using more patients in their practice? What is kind of like the biggest rate limiter, you think?
I think primarily the rate limiter is just getting people comfortable with using a mechanism of action. They're not used to necessarily implementing REMS programs. Certainly, the centers of excellence have done that now, and for them, it's pretty routine. In the general practice world, a simple REMS program will make it much simpler for them to use. We hope to have a simple REMS accompanying Aficamten.
I think confidence in how you use this drug and the predictability of its effects, all of those things will translate. I think once people start using this in their practice and they get the really positive patient feedback that comes back from it, you generally see expansion of use across the board.
Yep, yep. Obviously, I mean, Camzyos has started to really kind of tick up and has had a really good quarter this past quarter, which I think is important to highlight.
Yeah. I might add, Camzyos is doing just fine. That drug should do north of a billion dollars in sales this year. As a next in class opportunity, it is our responsibility to help grow the category and as could be enabling of ultimately preferential share, but doing so in a way that is addressing what any good next in class drug should be focused to, which is convenience, ease of use, flexibility, safety, tolerability, the things that drive ultimately best in class profiles. That is what we are doing. At Cytokinetics, we have an opportunity to do it right the first time.
We're not having to redeploy legacy systems in specialty distribution or patient experience hubs, but rather design them from the ground up specific to this market opportunity. Jeff Lotz is our Head of Sales. He's here in the audience. He and his team have been on the ground for over four years now readying for this opportunity. They've understood the marketplace, the dynamics. They've understood how best to design patient experiences. We've been interacting with payers. We're thinking about how to make this from the specialty distribution standpoint bespoke to the market needs. We've done a lot of market research both before and after we had pivotal data to best understand what customers need, not just customers in general, but the top tier segment who are the influencers to others.
Our goal is to get center of excellence, high volume prescribers comfortable with Aficamten and ultimately ripple that out into the community. Unlike today where there's roughly 700 physicians accounting for 80% of prescriptions for Mavacamten, our goal is to open the aperture on more prescribers who can more comfortably feel that they're doing the right thing by their patients.
Yeah, makes sense. You mentioned preferential share kind of over time. I guess in the context of 2026 and year one, what do you think a win looks like? Do you think you can get preferential share kind of within new patients next year, or is that too ambitious?
I think that's a good objective. I do think that people need to understand that in cardiology, sometimes things take a little longer. Patients will be prescribed the medicine, and it may take upwards of one to two, two to three months for that to translate into commercial returns. We're guiding to mavacamten's first year as could be reasonable in terms of four successive calendar quarters for what we might anticipate as well as we enter the market, but hopefully achieve an asymmetric growth soon thereafter. We're looking at numbers of physicians who are prescribing, numbers of new physicians who are prescribing and persistently, and patients in terms of new to brand and also how quickly we can convert them from free drug to commercial drug. These are the measures of launch velocity that we'll be monitoring and assessing as we go forward.
That's what we'll be focused to. I don't want to get too far out over our skis in terms of guiding to sales numbers. We're not going to do that.
Yeah, yeah, fair enough. It sounds like you think the preferential share dynamic may play out relatively quickly in terms of what that may shake out like.
Certainly new to CMI.
Yeah, new to CMI. Okay, great. I guess maybe the last question on the launch, because I do want to talk about Acacia. Maybe Sung, obviously you guys have ways to kind of fortify the balance sheet still. Do you think you're well funded to launch this drug? Do you guys need to raise again? What are sort of the options there as you think about this launch in the pipeline?
Yeah, so James, we can't rule out the need for additional capital in the future. We're going to constantly evaluate that as we're launching Aficamten. What I can share is by the end of this year, we expect to have a very strong balance sheet with $1.2 billion in cash and investments. We would have access potentially to further capital, as Robert mentioned in his prepared remarks via Royalty Pharma. There's a Tranche 7 loan out there for potentially $175 million. We believe we're well capitalized ahead of the launch. Importantly, this will allow us to build infrastructure in Europe to prepare for a launch in Germany, as well as to advance important pipeline programs such as Omecamtiv Mecarbil, Reldemesemtiv, and CK-586, in addition to advance our research programs as well.
I'm really pleased with how we're going to enter next year in terms of our balance sheet positioning.
Yep, makes sense. Awesome. In the last seven minutes or so here, I do want to jump to Acacia. Obviously, that's gotten a lot more investor attention, and I think especially post ESC, where people were a little surprised at how close Odyssey was. We saw some more data this past weekend at AHA. Just curious kind of your takeaways from all of this detailed data that's accrued from Odyssey and how that kind of informs your confidence in Acacia next year.
The more we see from Odyssey, the more it reinforces optimism that Acacia could deliver, both from the primary and now more secondary, as well as ad hoc analyses. I think it supports something that Fady has been saying all along that has a lot to do with exposure and continuity on treatment as to how these patients may benefit, and biomarkers are good leading indicators of clinical endpoints. Maybe I'll ask Fady to elaborate, especially as we saw more data this past weekend.
Yeah, I think as we saw the primary data presented at ESC, you saw positive effects on both primary endpoints, KCCQ and Peak VO2, with KCCQ result being confounded by a very large placebo effect in KCCQ, much larger than it's been used in hundreds of trials. It was kind of an outlier. Don't ask me to explain why, because I don't know. History would say that that's not a typical placebo response. There was also the revelation that about 25 of the patients had treatment interruptions or EFs less than 50% or discontinuations and so forth. You had a result that was confounded really by exposure to the drug.
That was, I think, confirmed to me anyway this weekend when there was an analysis presented of Odyssey where they split the patient population to those with ejection fractions that were less than 65%, recognizing at 50% you have to interrupt treatment, and those with ejection fractions that are greater than 65% or more. What was striking was how different the exposures were in those two groups. The lower ejection fraction group had an exposure that was two and a half times lower than the higher ejection fraction group. When you looked at how the outcomes performed in those two groups, you saw meaningful improvements in KCCQ and Peak VO2, the two primary endpoints in our trial, in the higher ejection fraction group corresponding with the higher exposure.
It's a simple mantra, but the right dose and the right patient at the right time is always what you have to focus on. I think when you get to the right exposures, you get the intended clinical effect. It's bolstered. The fundamental premise for pursuing this, which they also demonstrated, is that you see improvements in NT-proBNP, you see improvements in diastolic parameters of function in the echo data that are the underlying therapeutic hypothesis for why it should be effective in the first place. Everything's kind of consistent with that.
Yep, yep, that makes sense. Yeah, the data this weekend were really interesting from Odyssey. Obviously, you've shown Forest data where most patients can dose up. Treatment interruptions are similar or down titrations, LVF less than 50% rate are similar to what you've observed in obstructive.
I guess what's your confidence that that will translate in Acacia as well? Is there anything you can see in blinded safety data in terms of these ejection fraction drops that would imply patients are not discontinuing therapy?
Yeah, I mean, we're blinded to the echo data, so we can't tell what happens there. The only time we see anything is if the EF falls below 40%, the patient has to interrupt. I can tell you that happens extremely rarely. We can't really tell the ones above that. I think our experience in the phase two data just tells us that most of the patients got to the highest doses without really any treatment interruptions. I don't think there's any reason to expect us to see anything much different in Acacia.
Yep, yep, that makes sense. Great. I guess as we think about the trial, there's dual primaries of PVO2, KCCQ. Does it have to be a P value on both endpoints? Could it be P value on KCCQ trending on PVO2? Just curious if you could help kind of frame what is technically a win both for success, but also regulatory-wise.
There is success from a clinical standpoint and a trial design. There is success from a Wall Street standpoint. There is success from an FDA standpoint. They aren't necessarily all the same. The study is a win if we hit on one of the endpoints, but it would certainly be challenging from a regulatory standpoint if we hit on one and the other is moving in the wrong direction. We'd like to think that we could hit on both. That would certainly make the regulatory conversation more straightforward.
I think we're in a good position having designed this study with co-primary endpoints to be enabling of a win if we hit on either. Based on the Odyssey results where we've seen trends, but not statistically significant on both, and for reasons relating to dose density and otherwise because of dose interruptions, maybe that didn't deliver. We think that Acacia could. I don't know if there's anything you want to add.
Yeah, yeah. And then maybe just on KCCQ, obviously it seems like, like you mentioned, that placebo response was an outlier versus everything else we've seen. Do you think so many patients interrupting treatment, does that just confound? Could that confound placebo in any way? Just curious if you have any theories of why that might have been an outlier.
Yeah, I mean, I don't really want to speculate. I didn't conduct their trial. I'm not privy to that kind of data that would even give me a reason to speculate. I know our own experience with KCCQ. We've now used it ourselves in four different clinical trials spanning over nearly the last seven years. You have to train the sites in how to administer it. You have to tell the patients that this is not just a barrier for you to fill out to get to the doctor. Like most doctor's offices, you get a piece of paper, you fill it out as quickly as you can. You tell them this is actually a primary endpoint of the trial. It's important. Take the time, all the time you need. Tell the sites to give the patients all the time they need.
The same person administering it each time and so forth. Hopefully we've learned how to do it right and we'll get a typical response that you see.
Investors don't always understand that clinical trials are like any experiment. It has everything to do with study conditions, and that includes where you do the study, who does the study, how well trained they are, how much fidelity there is in the way in which they conduct the exercise assessment, KCCQ monitoring improvements. These are things that you have to control for and not just plug a drug into a study and expect it to produce an outcome. Clinical operations and study conduct is an essential competency at companies like Cytokinetics. Fady, maybe you can speak to who's been involved in doing these studies and the continuity and the consistency across team and centers.
Yeah, we've had an experienced team in place now for since the beginning of the program, almost six years ago. They've conducted Redwood, they've conducted Sequoia, they monitor Forest, they are in charge of Acacia. It's a team of physicians and clinical operations folks, statisticians. Particularly the physicians in our case are HCM experts. They've treated patients in their past clinical lives. They've run clinical practices. When we qualify patients for Acacia, they look at the qualification, the entry criteria, as well as the echocardiograms to ensure that what they're seeing is a patient that has hypertrophic cardiomyopathy, non-obstructive hypertrophic cardiomyopathy. I think just as I said, our conduct of Acacia, I think, is you're not going to be able to fault the conduct or the trial design. It's what the result we get will be something we can believe.
Yep, yep, makes sense. Makes sense. Execution matters, especially I imagine for peak VO2 as well. Maybe I know we're just a minute over, but last 30-second question in terms of the AHA data this weekend. I think BMS highlighted those patients had generally milder disease that did better. Is that surprising to you? Two, is that kind of how you would want to enroll Acacia anyways? Curious what you think those implications are.
Yeah, I'm not so sure how different the "milder disease" was. Generally, people that have higher ejection fractions are going to look a little better. We already recognize that we didn't want to enroll people with ejection fractions as low as 55. Our entry criteria require EFs of 60 and above. So we might, I think, again, probably enroll patient population that should hopefully be most responsive to the drug.
Yep, makes sense. Great. Thanks everyone for joining and thanks for you guys being here. We appreciate it.
Thank you.
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