Cytokinetics, Incorporated (CYTK) Earnings Call Transcript & Summary

Good morning, and welcome, ladies and gentlemen, to Cytokinetics conference call announcing the top line results of REDWOOD-HCM. [Operator Instructions] I will now turn the call over to Diane Weiser, Cytokinetics Senior Vice President of Corporate Communications and Investor Relations. Please go ahead.

Welcome, everyone, and thanks for joining us on our call today, which will focus on the top line results of REDWOOD-HCM, the Phase II clinical trial of CK-274, our next-in-class cardiac myosin inhibitor. Robert Blum, our President and Chief Executive Officer, will begin with an overview of today's announcement. Then Fady Malik, our Executive Vice President of R&D, will present the top line results and our planned next steps in the development program for CK-274. Robert will then provide closing remarks before we open the call to questions. Please note that portions of the following discussion, including our responses to questions, contain statements that relate to future events and performance rather than historical facts and constitute forward-looking statements. Our actual results might differ materially from those projected in these forward-looking statements. Additional information concerning factors that could cause our actual results to differ materially from those in these forward-looking statements is contained in our SEC filings. We undertake no obligation to update any forward-looking statements after this call. And now I will turn the call over to Robert.

Thanks, Diane, and thank you to everyone for joining us on the call today. Today is a very important day for the potential treatment of hypertrophic cardiomyopathy and especially the community of patients and clinicians who are challenged by this severe cardiovascular disease. It's also an important day for Cytokinetics and our shareholders. In the past several months leading up to today's announcement regarding the results of REDWOOD-HCM, we spent a lot of time with analysts and investors discussing what good would look like. Today, I believe we can speak with assurance that these results are solid and augur well for our next-in-class objectives for CK-274. In fact, these top line results of REDWOOD-HCM meet what were our already high expectations for this dose-ranging trial and our next-in-class objectives. As the pioneers in the science of modulating cardiac myosin, it's rewarding to see that the physiochemical properties that we prioritized in optimizing CK-274 are translating into clinically meaningful results for patients with HCM. As you know, CK-274 was optimized for onset of action, rapid reversibility of effect, minimal drug-drug interactions, favorable tolerability and ease of dose titration for personalized dosing. REDWOOD-HCM delivered on those objectives. As Fady will elaborate, the trial showed that CK-274 produced substantial and statistically significant reductions from baseline compared to placebo in the average resting and post-Valsalva left ventricular outflow tract pressure gradients. Importantly, treatment with CK-274 in REDWOOD-HCM was well tolerated and appears effective within 2 to 6 weeks of the start of dosing with no treatment interruptions or treatment discontinuations due to a reduction in left ventricular ejection fraction. These results, coupled with the positive results from GALACTIC-HF, our Phase III trial of omecamtiv mecarbil in patients with heart failure, are further catalyzing the transformation of Cytokinetics from an R&D company to one that we expect will also go commercial. As we look to potentially launch our first medicine, a first-in-class cardiac myosin activator next year, we can now also plan to advance our next-in-class cardiac muscle inhibitor into Phase III later this year. Together, these 2 drug candidates represent innovations in muscle pharmacology for tough-to-treat cardiovascular diseases and at the source of the problem, impaired contractility or excessive contractility. As a reminder, there are no currently approved medical treatments that safely address the underlying root cause of HCM or heart failure, so we're extremely enthusiastic to advance CK-274 to a Phase III clinical trial by year-end. And at the same time, we'll proceed toward our goal of submitting an NDA to the FDA for omecamtiv mecarbil. And with that, I'll turn the call over to Fady to present the top line results of REDWOOD-HCM.

Thanks, Robert. Before I go through the slides, I'd like to thank our team at Cytokinetics as well as the investigators and clinical site coordinators for their commitment to REDWOOD-HCM, particularly given the challenges they overcame enrolling and conducting a trial in the midst of a global pandemic. As you know, we've been pursuing modulation of the sarcomere for 2 decades now and have discovered and have entered into development a number of cardiac myosin modulators as well as troponin modulators that changed the contractility of the sarcomere, either increasing it as in omecamtiv mecarbil or decreasing it as in CK-274 and 271. This has formed the basis of our drug discovery engine for the last 20 years. Focusing on hypertrophic cardiomyopathy, a condition of excessive contractility driven by mutations in the sarcomere, this is a disease that is the most common genetic cardiomyopathy and has a diagnosed clinical prevalence somewhere between 100,000 and 280,000 individuals. This is in the absence of therapies that directly address the root cause of the disease. And we believe, in fact, that there's a diagnosis gap with many more patients whom -- for whom treatment may present an option once treatments that are more targeted to the cause of their disease become available. CK-274 was developed as a next-in-class cardiac myosin inhibitor with specific objectives in mind. It's an allosteric inhibitor of cardiac myosin, and it's intended to reduce the cardiac contractility of the sarcomere. It was optimized for its onset of action with the intent to have it reach steady state within 2 weeks to enable flexible dose titration, reversibility of its effect, minimizing the potential for drug-drug interactions, including a favorable safety profile and, in particular, focusing on the ease of titration for personalized dosing. We optimized it to maximize the shallowness of the PK/PD response as might enable flexible optimization of dose. REDWOOD-HCM began in January of 2020 as a clinical trial in patients with hypertrophic cardiomyopathy, who had a resting or provoked gradient of greater than 50 mmHg. Patients were randomized in a 2:1 fashion to CK-274 or placebo and received up to 3 doses of CK -- of study drug rather. These -- in Cohort 1, the doses were 5, 10 and 15 milligrams. And in Cohort 2, the doses were 10, 20 and 30 milligrams. Patients began treatment on day 1 at the lowest dose, had an echocardiogram at 2 weeks and if they hadn't met treatment targets, would escalate to the next higher dose. At week 4, they underwent another echocardiogram. And again, if they had not met treatment target, they would escalate to the third and final dose. They continued their highest dose until week 10, at which time drug was withdrawn. And there was an echocardiogram at 12 weeks to look at reversibility and a safety visit at 14 weeks. The study enrolled a total of 41 patients, 13 patients on placebo as combined in both the placebo groups of Cohort 1 and Cohort 2 and the rest receiving treatment with CK-274. As you can see in Cohort 1, 4 patients stopped at 5 milligrams, 5 patients stopped at 10 milligrams, and 5 patients got to 15 milligrams. In Cohort 2, the low dose was 10 milligrams, and 9 patients were adequately treated at that dose. 4 received 20 milligrams, and 1 escalated up to 30 milligrams. The baseline data in these groups were well balanced. You see there with ejection fraction about 74%. The resting gradient, approximately just above 50, and the Valsalva gradient between 74 and 84 mmHg. This graph shows the number of responders in each group per the responder definition to the right of the slide. Resting -- that is the resting gradient need to be less than 30 mmHg and the post-Valsalva gradient, less than 50 mmHg at week 10. That was -- those were substantial reductions from where they started, as you saw in the previous slide. And in Cohort 1, we achieved 11 patients out of 14 with meeting the responder definition. Cohort 2, 13 out of 14 or a 93% responder rate compared to 1 patient out of 13 in the placebo group. This graph shows the change in resting gradient as a function of time. As you remember, patients began at day 1. And at week 2 and 4 had dose changes, potential dose changes and then continued to the end of treatment at week 10. One sees an immediate at week 2 decrease in the resting gradient, which reaches its maximum effect at week 6 and is sustained out to week 10. The actual numbers are in the table below, and you can see the p-values for comparison of the treatment effect to placebo at each time point were highly statistically significant. The second plot here shows the effect over time on the post-Valsalva left ventricular outflow tract gradient. And again, you see a response, which begins at 2 weeks, reaches its maximum effect at 6 weeks and is maintained out to 10 weeks. Again, these numbers are highly statistically significant from week 6 onwards. And you see there a bit of the dose dependence in that the second cohort there in the green triangle had a greater earlier onset of action and reached ultimately a greater treatment effect, reducing the gradient down to approximately 30 mmHg. Important, the safety data are summarized on this slide. The incidence of adverse events on CK-274 were similar to placebo and were all graded mild or moderate. There were no treatment-related serious adverse events reported by the investigators on CK-724 -- 274. There were no patients who received CK-274 in Cohort 1 who had an LVEF of less than 50. And in the second cohort, we had one patient who had an LVEF at baseline of 58%, was up titrated to 20 milligrams and experienced a transient reduction in LVEF to less than 50, remaining above 40% and requiring a down titration back to 10 milligrams. 2 weeks later, their echo showed that their EF was above 50%. There were no treatment interruptions, no treatment discontinuations with CK-274 that occurred across both cohorts. Those summarize the top line data from REDWOOD-HCM, but I'd also like to just remind you that we're conducting an open-label extension trial called REDWOOD-HCM OLE. This trial is now underway and is beginning to enroll patients from Cohort 1, and patients from Cohort 2 will be eligible for the study as well. The primary endpoint is safety. The secondary endpoints will look at the long-term effects of CK-274 on gradient and pharmacokinetics. There's also a cardiac MRI sub-study to assess changes in cardiac morphology, function and fibrosis. Patients will begin at the lowest dose and will titrate upward. The initial dose was informed by the first cohort and will be -- the highest dose will be informed now by the sum of the data from Cohorts 1 and 2. We have begun preparations for Phase III some time ago and began to interact with the FDA around finalizing a protocol and a -- in the Phase II meeting. We've already conducted a Type C meeting with FDA and are generally in agreement in terms of the protocol design. And there's an upcoming end of Phase II meeting in Q3 to finalize the dose selection rationale. The overall program is shown here, and we are now leaving Phase II with the completion of Cohorts 1 and 2. I'll remind you, we still have a third cohort ongoing that looks at CK-274 in patients treated with disopyramide. It's background therapy. This will -- is enabling the design of a pivotal Phase III trial, which we expect to begin at the end of the month. As we indicated in our press release this morning, we intend to take doses of 5, 10, 15 and 20 milligrams forward into the Phase III study. This will allow for patients to achieve their maximum treatment effect at the lowest effective dose. The extension study will run in parallel with these studies, and we are also considering now embarking on a study in patients with nonobstructive form of HCM, as you can see there on the bottom. We believe that there is an opportunity to address hypercontractility in several conditions, either obstructive HCM, a nonobstructive HCM but also in a subset of heart failure patients with preserved ejection fraction, whose underlying cause of their disease is driven by hypercontractility of the left ventricle. This forms basis for expansion of the population that may be addressed by this mechanism of action. And with that, I'll turn it back to Robert for closing remarks.

Thank you, Fady. As I said at the start of the call, this is a great day for patients, clinicians, Cytokinetics and our shareholders. More than 20 years ago, Fady had a vision for our muscle biology pipeline, and we've been pursuing that vision tirelessly for 2 decades. Today, we're pleased to share these encouraging Phase II results for CK-274 that punctuate our plans to advance 2 potential new medicines that we believe can change the treatment landscape for the severe cardiovascular diseases of HCM and heart failure with reduced ejection fraction. By harnessing the power of myosin modulation, these new mechanism drug candidates, one that inhibits cardiac myosin and one that activates cardiac myosin, may help these patients return to activities of daily living like going to the grocery store, playing with their grandchildren or enjoy a walk with friends. We look forward to sharing the full results of REDWOOD-HCM at a future medical meeting and beginning the Phase III clinical trial of CK-274 by year-end in patients with -- are executing on our goals for submitting an NDA to the NDA -- to the FDA for omecamtiv mecarbil in the second half of 2021. With that, operator, we can open up the call to questions.

[Operator Instructions] Our first question comes from Jason Butler with JMP Securities.

Congrats on the results. First off, can you maybe speak to the patient population that you plan to study in the Phase III study? How it would compare to both REDWOOD and the mavacamten EXPLORER trial? And specifically, in terms of disease severity or risk -- sorry, risk profile of the patients you may include or exclude? And then I have a follow-up.

Yes. Jason, thanks for the question. I think in Phase III, what we hope to do is enroll a patient population that has substantial issues or issues with exercise tolerance. So ensure that they have reduced exercise tolerance, that they are potentially class -- more Class III-ish than II-ish and ultimately look for ensuring that symptomatic patients are treated with background therapy that has maybe then augmented by addition of CK-274 to the regimen. So I can't really -- I don't want to really tip our hand too deeply, but you'll see it later in the year, we'll elaborate as the trial gets underway. We'll certainly elaborate on why we think this Phase III trial will be distinct.

Okay. Great. And then obviously, you detailed your plans to meet with FDA in 3Q. Any plans to interact with European regulatory agencies in the near term or before you start the Phase III trial?

Jason, so yes, indeed, we expect to be engaging with regulatory authorities outside the U.S. as well. We'll have more updates on those matters later in the year.

Our next question comes from Joe Pantginis with H.C. Wainwright.

Congratulations as well. My first question, I just want to get a sense of the logistics of dosing. So -- and it's a little bit -- a couple of little things peppered in there. So first, what was the dose of the patient who saw the reduced ejection fraction? And how do you anticipate once you down titrated this patient or this kind of patient that they could stay on that lower dose beyond the treatment time period of REDWOOD? And also related to this, when you look at the doses achieved when you look at the 30-milligram dose in Cohort 2, I guess this wouldn't be necessarily viewed as a maximum tolerated dose because you didn't need to get patients to 30 mg. Is that correct?

Yes. I mean, I think in terms of your last question, I think for a very small subset of patients, they could certainly tolerate doses of 30 or even potentially higher. But as you can see, the number of patients become sort of diminishing returns and obviously, we want to take too many doses forward into Phase III. So we've settled on 4, which I think gives us a lot of flexibility. And if you recall, Cohort 1 study doses of 5, 10 and 15 milligrams had a responder rate of about 78%. And had we had a 20-milligram dose to add to that cohort, it theoretically would have matched what we saw in Cohort 2. So that's the rationale for taking 4 doses in the Phase III. As I explained, the doses, you can evaluate their effect every 2 weeks. And so by 6 weeks, you kind of evaluated 4 different doses. By 8 weeks, they should be at approximately at steady state. With regards to the one patient that you called out, I think as I mentioned, the maximum dose the patient received was 20 milligrams, at which point they down titrated back to 10. Now that patient had the lowest ejection fraction or one of the lowest ejection fractions on entry into the trial, 58% and theoretically, may have been even better served by the starting dose in the first cohort of 5 milligrams. But they finished the study out on 10 milligrams without any further issue.

Got it. And my second question is really going off of Jason's question as well. I mean, obviously, the elephant in the room here is everyone is going to be doing depending on how you look at it apples-to-oranges or apples-to-apples comparisons with mavacamten. And I guess the real question is here is A, you've delivered on the profile that you were looking to achieve with 274. So I guess, the open question right now is the real-life importance of being able to see these dramatic drops more rapidly within 2 weeks, especially in those charts that you've shown?

Yes. I think, Joe, as you can expect, we're not going to make those comparisons to Bristol-Myers Squibb's mavacamten. Instead, we're focused to CK-274 and what we think these results demonstrate. We think they do underscore what were the objectives we had in designing CK-274 and optimizing and characterizing it for certain properties that we believe have been validated, both preclinically and clinically. And it's with that in mind that we're advancing what we hope can be a next-in-class compound.

I had to ask anyway, but congratulations.

Our next question comes from Salim Syed with Mizuho.

Congrats on the data. Looks great. I've had a couple of questions. The one patient that you had to down titrate to the 10 mg. Could you just clarify for us, did you include this -- did this patient hit target gradient when they were at 20? And they -- were they included in the 92.9% figure? And were -- and then I guess related to that, did they maintain target gradient once you down titrated them to 10 mg?

The answer to both of those is yes.

So they -- so what -- they hit target gradient first at the 20 mg. And then when you down titrated them, you were able to get them...

The reason they up titrated to 20 was because they hadn't met target, right? And then their EF fell below 50, remained above 40. So despite the fact that they met target, they had to be down titrated because of their EF. And as we said earlier, this is a trial where we wanted to see a dose-limiting effect at least in 1 or 2 patients, so we understood the reversibility of the drug. The patient went back down to 10. And in fact, as we know, gradients can be variable, but they stayed -- their gradient stayed below target for the rest of the study, and they finished the study without any dose interruption, just with the change in dose. So very, very effectively showing the benefit of the reversibility of CK-274.

Okay. Great. And then, Fady, maybe you could just elaborate that. When you're thinking about monitoring, obviously, we saw patients hit ejection fraction sub 50%. With mavacamten, at least all the way out to 30 weeks, I think there are 4 different cases there. Clearly, you guys haven't had that issue outside of this one patient, which came in with the low EF to begin with. Could you just speak to monitoring how you're thinking about this? Would it be for patients starting with a low EF? Or do you think you can have no monitoring whatsoever if this thing were to proceed into Phase III and then the label?

I think it's a little early to think through all those details. I'll point out that patient with low EF, that's one good reason to start 5 milligrams rather than a 10. We saw 5 milligrams was a pretty effective dose for about 1/3 of the patients in Cohort 1. And perhaps this patient would have stopped at 5 milligrams and stayed there under different circumstances. So I think in a -- I think the important thing to recognize is not so much did the patient dip below 50 or not. This is an asymptomatic echocardiographic finding. It's really the question of how disruptive is it to therapy and how do you deal with it. In this case, we don't expect necessarily you'll need to discontinue drug. You can continue on a lower dose and ultimately, have the confidence that their ejection fraction would return to the normal range with the down titration of dose. So I think those are the important things to focus on. And I think those were elaborated here in the study.

Congrats again.

Our next question comes from Jeff Hung with Morgan Stanley.

Congratulations on the data. I just had one. I guess, in Cohort 2, I know that the resting LVOT gradient already met the target goal by week 2. But the level at week 6 seems particularly low relative to weeks 4 and 10. Can you just talk about anything notable that you saw from week 6 to 10?

Yes. I mean, I think with regards to the gradient over time, it was essentially flat from week 6 to 10. We didn't do any echoes in that intervening period. And the changes from week 2 to week 6 in Cohort 2, for instance, were probably just within statistical variability. You can see with Cohort 1, where we started with a lower dose, that it took a little longer to get to that maximum effect at 6 weeks, and that's to be expected. And so I think the benefit of just having a predictable onset of effect that accumulates as you increase dose is one of the strengths of CK-274.

Our next question comes from Charles Duncan with Cantor Fitzgerald.

Congrats on this data. Robert and Fady, quick question, though, regarding Phase III. I know that you haven't yet had the meeting with agency. But is that scheduled? And then secondly, can you provide us any color on steps to operationalizing that Phase III regarding, say, clinical site selection and then timing?

Sure. So I'll take the first one and ask Fady to respond to the second. So we have already engaged FDA in a Type C interaction around our plans to move forward with CK-274. We still have an end of Phase II meeting to be occurring. That will be occurring soon, but we already have, we believe, a path forward that would be enabling of our planning to start Phase III by the end of this year. Fady?

Yes, Charles. I mean since the Cohort 1 data, interim data we saw in December last year, we've been executing at risk basically, anticipating that we would move forward into Phase III, as we've, I think, been pretty clear. So drug manufacturing, drug product manufacturing has been underway and is on time line to be able to supply the study. We've begun to initiate sites in countries around the world with prestudy start-up activities. We have a protocol that is in its final form. And I think all of those augur well for the start-up of Phase III by the end of this year.

Okay. And then with regards to the open-label extension of this study, I guess I wasn't clear. Has that begun? And can you give us a sense of the enrollment thus far?

Sure. It has begun. And as I said, up until this point, only really patients in Cohort 1 were eligible to get into it. So it's still in the study start-up phase. We've got a couple of sites activated. There are more on the way. And as we do that, more patients will be able to get in. We've had a few patients enrolled already. But I think the main impediment to patient enrollment just really is getting the sites activated.

But you detect a fair amount of interest from these sites?

Oh, absolutely.

Yes.

Everyone who's enrolled a patient in REDWOOD would like to be part of the open-label extension.

Our next question comes from Dane Leone with Raymond James.

Congratulations on the data. I'll just leave 2 quick questions from my end. Firstly, sorry, if you already said this connectivity issues. Did you -- were you able to disclose what the baseline Valsalva LVOT gradient was for the patient that did have the ejection fraction event and needed -- went from 20 milligrams to 10 milligrams? And then were you able to disclose what the end of study week 10 LVOT gradient was for that patient? And then I have one follow-up.

Yes. Sorry. I mean, top line data, we didn't really get into those details, Dane, but I'll just reiterate what I said before that they had met their target. And they -- by the end of the study, they were one of those responders.

Okay, great. And then the second question is relative to this study, how do you think about what protocol guides dose titration in the Phase III study, given you'll be using a VO2 endpoint and presumably CPET?

Well, I mean, dose -- correct me if I don't have your question right. But dose titration in Phase III will follow the same sort of scheme that we used here in Phase II. It will be guided by a reduction in resting in Valsalva gradient as well as an evaluation of ejection fraction. And we'll make that assessment every 2 weeks during the dose titration phase and the patient's dose will be adjusted accordingly. We won't use exercise tolerance to adjust dose, obviously. I think that's a bit challenging, but exercise will be assessed at the end of the study to show that we've had a treatment effect there.

Our next question comes from Carter Gould with Barclays.

Congratulations on the data. But I guess I'll start first off on the nonobstructive plans there. Any opportunity there to kind of hit the accelerator on the back of today's great data? And then also for Fady, just in terms of the third cohort, are you going to now be expanding the range of doses that will be evaluated there or not?

So as to the first question, we're not yet elaborating on our plans in other indications. But clearly, this increases our conviction to advance CK-274 not only in obstructive disease, but also nonobstructive and also other indications. So as we look forward, we now have demonstrated CK-274 has those properties that we think would render it next-in-class across an array of indications. So yes, you can assume that we'll be advancing for it in those matters, too. More information forthcoming.

And the -- remind me the second question, Carter, sorry.

Cohort 3.

Around the third cohort. And if you're going to -- I believe when that was originally disclosed, you were only exploring the doses that were also explored in Cohort 1. Will that now also include higher doses?

Yes. Thanks, Carter. I don't think we'll adjust the doses in the third cohort, just the doses are 5, 10 and 15. As you saw, those were pretty effective doses. I don't think the issue really is adding another dose of 20 to that to complicate the ongoing study conduct is really necessary. So we'll just focus on those 3 doses. That wouldn't preclude dosing those patients with 20 milligrams, should we include them in Phase III since we have the data. We'll have the data from those other doses and the data from the healthy patients not on disopyramide in Cohort 2 to kind of make the case for all those doses.

Great. Congrats again.

Our next question comes from Graig Suvannavejh with Goldman Sachs.

Robert, Fady, congrats on the data. Maybe a bigger picture question for me. Just in terms of this data, how does this inform your potential BD strategy on whether you're going to be partnering this as part of perhaps a portfolio with omecamtiv? Or does this data basically strengthen your conviction in launching this product on your own? Just any thoughts there on how you think about going forward here?

Sure. So a very good question. As I mentioned, we already had high expectations for CK-274 and results from REDWOOD, this is confirming of that. So already we had intended with our partnering strategy to capitalize on what we expected would be positive results from REDWOOD. So that hasn't changed. And we continue to seek a partner in Japan and potentially also in Europe as would be enabling of us to their -- with a partner, build franchises similar to that, which we expect to do on our own in the United States. So omecamtiv mecarbil is a cardiac myosin activator, CK-274 is a cardiac myosin inhibitor. We see that there are great synergies, both from the R&D and the commercial standpoint. And we're looking for partners that share that view. That hasn't changed.

I'm showing no further questions in queue at this time. I'd like to turn the call back to Robert for closing remarks.

Thank you, operator, and thank you to all the participants on the call today. This is a milestone day for Cytokinetics and its shareholders, but also, more importantly, for patients and the physicians who treat them, especially as they suffer with severe cardiovascular diseases. The science of cardiac myosin modulation, both with activation with omecamtiv mecarbil and inhibition with CK-274, is advancing. And we believe these results announced today from REDWOOD-HCM provide further wind in our sails as we'll continue to move CK-274 forward now with plans to begin a Phase III trial before the end of the year. These results are positive and encouraging and validating already of things that we've been aiming towards. We look forward to keeping you abreast of our continued progress. We welcome your comments and other interests you might have. And with that, operator, we can conclude the call.

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