Good afternoon, and welcome, ladies and gentlemen, to the Cytokinetics Third Quarter 2019 Conference Call. At this time, I'd like to inform you that this call is being recorded and that all participants are in a listen only mode. At the request of the company, we will open the call for question and answer after the presentation. I will now turn the call over to Diane Weiser, Cytokinetics' Vice President of Corporate Communications and Investor Relations. Please go ahead.
Happy Halloween, everyone, and thanks for joining us on the call today. Robert Blum, our President and Chief Executive Officer, will kick off the call with a review of our key priorities. Then, Fady Malik, our EVP of Research and Development, will provide updates on key developments for omecamtiv mecarbil, our cardiac myosin activator under our collaboration with Amgen as well as for CK-two seventy four, our wholly owned cardiac myosin inhibitor now proceeding from Phase 1 to Phase 2 development. Then Robert Wong, our VP and Chief Accounting Officer, will provide a financial overview for the quarter and Qing Zhang, our SVP and Chief Financial Officer will discuss corporate development strategies. Andy Wolf, our SVP and Chief Medical Officer, can't be on the call today.
So Robert will then cover off on updates relating to reldesemtiv, our fast skeletal muscle troponin activator under our collaboration with Astellas before concluding with thoughts on the company's outlook and expected milestones for the remainder of the year. 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 may 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 the call.
And now I'll turn
the call over to Robert. Thank you, Diane, and thanks again to everyone for joining us on the call today. We continue to make good progress against our priorities during the Q3. And to begin today's call, I'd like to remind everyone what those priorities are in order to provide some context for the updates you'll be hearing about from the team. Currently number 1 remains the advancement of omecamtiv mecarbil, our cardiac myosin activator, currently the subject of 2 ongoing Phase III clinical trials under our collaboration with Amgen.
As you may know, enrollment in GALACTIC HF completed in July. That in and of itself is a big achievement considering the number of patients, sites and countries that participated in this important clinical trial. Looking forward, based on the accrual of clinical endpoint events in the trial, we expect the 2nd planned interim analysis to occur in the Q1 of 2020. While we certainly don't expect the trial to conclude as a result of that analysis, we do recognize that that is a possibility that we need to be ready. With that said, both GALACTIC HF and METEORIC HF continue to be on track to read out results in 2021.
Given the proximity to the results of these key trials, Amgen and Cytokinetics have stepped up commercial readiness activities, including work streams focused on matters such as market access, health economics and medical affairs. And we'll elaborate on that in a moment. Priority number 2 is the advancement of CK-two seventy four, our wholly owned cardiac myofin inhibitor for the potential treatment of hypertrophic cardiomyopathy or HCM. And we expect to begin Phase 2 by year end. As we said, we believe CK-two seventy four represents a potential next in class drug candidate that has now demonstrated a distinct clinical profile in healthy subjects consisting with that which we observed in our preclinical work that we hope to translate to a therapy with optimized dosing, ease of titration and symptom relief for HCM patients.
In a moment, Fady will discuss the significance of the Phase 1 data in healthy volunteers and how the properties we have confirmed will shape our approach to Phase 2 and beyond. Priority number 3 is the advancement of Reldesemt, our fast skeletal muscle troponin activator, and we expect to potentially begin a pivotal Phase III clinical trial in patients with ALS no sooner, but still in the latter part of 2020. In the last quarter, we presented additional results from FORTITUDE ALS, which provide further support for advancement of this drug candidate as a potential new therapy for patients suffering with ALS, especially in light of the FDA guidance, which recently published. I just returned from productive meetings with our partners at Astellas, and I'll share an update regarding this program and our collaboration later in today's call. So the company is well positioned with the advancement of our 3 lead drug candidates in later stages of clinical development.
In addition, we're also encouraged by recent developments relating to our cardiac troponin activator, partnered with Amgen, in Phase 1, and now 2 more potential drug candidates advancing in IND enabling studies. Given the opportunities to impact a wide array of cardiovascular and neuromuscular diseases associated with impaired muscle function and muscle weakness, With our industry leading pipeline of muscle activators and inhibitors, it's especially rewarding to note that the company does not pivot on any one single program and is in an excellent position to deliver on the promise of our biology and its related pharmacology for patients. With that, I'll turn the call over to Fadi to elaborate on key developments in our cardiovascular program. Thanks, Robert. The most important developments in our cardiovascular programs this quarter centered around completing enrollment in Flakkuk HF and beginning to advance CK-two seventy four into Phase 2 clinical development as a result of supportive and encouraging data coming out of the Phase 1 study in healthy volunteer.
I'll address both of these developments starting with Omecamtiv and GALACTIC HF. On our last call, we discussed the breadth of enrollment of more than 8,200 heart failure patients in GALACTIC HF, and this is that this now represents one of the largest outcome trials ever conducted in heart failure. So why is this important And how is the treatment landscape in heart failure changing as omicancer macarbil gets closer to the finish line in this trial? While it's an exciting time in the treatment of heart failure, with newer medicines like Entresto being added to the standard of care and existing medicines like the SGLT2 inhibitor recently demonstrated reduced risk for worsening heart failure and cardiovascular death when added to the standard of care. These developments underscore the continuing burden of heart failure and the opportunity to improve patient outcomes with new approaches to treatment.
With this backdrop and given our having enrolled over 8,200 patients in GALACTIC HF, We are hearing increased enthusiasm for the clinical community and the thought leaders for the important potential omicamcinocarbil may represent to heart failure therapy. Its therapeutic rationale and development make it the 1st and only heart failure medicine specifically developed to treat the fundamental problems for these patients that is the inability of their hearts to pump effectively. At such, chilmicamten mecarbil has the opportunity to become foundational in treating heart failure with reduced ejection fraction. In GALACTIC HF, we've now enrolled we now have over 10,000 patient years cumulative exposure with a number of patients having been on therapy for over 2 years. The DMC recently held one of their regular meetings and again recommended continuing the trial without changes.
We now look forward to the 2nd interim analysis, which we expect to occur in the Q1 of 2020. As a reminder, this analysis will include an assessment for potential superiority as well as for futility. The futility boundary enables stopping the trials, there's no chance for success for it to continue, while the criteria for superiority are conservative. Thus, we think there's a small chance that the trial will stop for efficacy at this interim analysis, even if the benefit of omecamtiv mecarbil is consistent with the planning assumption. Additionally, it's important to note that the stopping boundaries provide guidance to the DMC and they did not represent binding rules.
The DMC considers all available evidence of its recommendations regarding child conduct and other considerations may support the consideration of colactive GHF even if numerical superiority boundaries are met in the primary on a planned analysis. Should the trial stop early, we certainly want to be prepared for next step. And so as Robert mentioned, together with Amgen, we're engaging in its worst range of pre commercial, medical and regulatory readiness activities to minimize time for the submission of marketing applications. Towards this end, our medical affairs activities are ramping up. Implementation of our field based medical strategies has begun with a successful deployment of our 1st medical science liaisons or MSLs.
As you may know, MSL was seen as the medical face of the company and they'll often be the 1st representative of Cytokinetics with whom the healthcare providers contact, particularly key opinion leaders, investigators and academics. The MSLs will be focused on scientific exchange, medical and disease state education in support of our ongoing clinical trial. In addition, Cytokinetics Financial Net Brands of commercial readiness activities in critical areas, including brand development and market research to prepare for a successful global launch of Omecamtiv mecarbil. Importantly, the companies are also implementing multiple strategies to generate real world evidence and targeted healthcare systems to complement expected clinical trials data and to support planned discussion with payers regarding the economic value of treatment with Omecamtiv mecarbil. Now moving to our cardiac myosin inhibitor program, we are pleased to recently present data from a completed Phase 1 study looking at escalating single and multiple ascending doses of CK-two seventy four in multi subject at the Heart Failure Society of America's 23rd Annual Scientific Meeting in Philadelphia.
The data were encouraging and consistent with what we've seen preclinically. The study met its primary and secondary objectives to assess the safety and tolerability of single and multiple oral doses of CK-two seventy four, describe the pharmacokinetics of CK-two seventy four and its pharmacodynamics as measured by echocardiography.
We also characterize the pharmacokinetic
and pharmacodynamic relationship or PKPD relationship between with OCK-two seventy four with regards to cardiac function and healthy participants. To quickly recap, the study demonstrated that CK-two seventy four was safe and well tolerated in healthy participants, no serious adverse events and no clinically meaningful changes in vital signs, ECGs or laboratory tests were observed. The pharmacokinetics of CK-two seventy four were generally dosed linear and state data appeared evident within 14 days of dosing. Left ventricular ejection fraction decreased in exposure dependent manner in the PKPD relationship for CK-two seventy four observed in humans was similar to that observed preclinically when adjusted for differences in protein binding. Specifically, the shallow exposure response relationship observed preclinically appears to translate to healthy participants and when combined with the drug's PK may enable flexible dose optimization in humans.
Importantly, steady state was achieved within 2 weeks of daily dosing and reversibility of effect was observed within 24 to 48 hours following 14 days of dosing. We are really pleased to see that these properties enable us to include a 2 week dose titration schedule in the upcoming Phase II clinical trial and they ultimately translate to rapid onset, ease of titration and rapid symptom relief for patients with obstructive HCM in the clinical practice setting. So with that, I'll now share more details about the planned Phase 2 trial, which we expect to begin by year end. The trial is called REDWOOD HCM, which stands for randomized evaluation of dosing with CK-two seventy four and obstructive outflow disease in HCM. We're excited to have selected for the name of the trial, this magnificent and enduring tree, a symbol of Northern California, as it not only reflects Cytokinetics roots in the region, but importantly reflects the strength, independence and enduring qualities we aspire to deliver to patients who are living with obstructive HCM and as may eventually benefit from our novel investigational therapy.
Redwood HCM will be a multicenter, randomized, placebo controlled, double blind, dose finding study in patients with symptomatic, obstructive HCM. Primary objective of the trial is to determine the safety and tolerability of CK-two seventy four. Secondary objectives are to describe the concentration response relationship of CK-two seventy four on the resting and postel salvo left ventricular outflow abrasion as measured by echocardiography during 10 weeks of treatment. We'll get into more details regarding specific endpoints of redwood AKTIA when we announced the start the trial expected later this quarter. 2 sequential cohorts with an option for a 3rd cohort will be enrolled.
Within each cohort, 18 patients will be randomized 2:one to active or placebo treatment and receive up to 3 escalating doses of CK-two seventy four or placebo based on echocardiographic guidance. Importantly, given the half life of CK-two seventy four, patients will receive an echocardiogram after 2 weeks of treatment at each dose to determine whether they'll be up titrated. The schedule should contribute to optimizing dosing and potential efficacy quickly, both in the trial and ideally in the clinical setting. Overall, the treatment duration will be 10 weeks with an echocardiogram to confirm reversibility of effect 2 weeks after the last dose. Redwood HCM is expected to enroll patients in around 20 investigated sites in North America and Europe.
We're currently finalizing operational plans to initiate the trial and expect it to open to enrollment in this Q4. We're enthusiastic to get the trial up and running and continue to receive positive feedback with similar enthusiasm from our investigative sites. And now Robert Wong will update you on our financials for the quarter.
Thanks, Patti. I'll first provide an update on cash, revenue and spending, and then Ching will review our corporate development strategy. More details of our actual results for the Q3 2019 are included in the press release, which we released earlier this afternoon. We ended the Q3 with $166,000,000 in cash and investment. Our revenue in Q3 2019 came from our strategic alliances with Amgen and Astellas.
For Amgen, we recognized revenues associated with the reimbursement of our development expenses related to METEORIC HF. For Astellas, we recognized revenue for reimbursement of our research activity as well as for development expenses incurred related to our closing out of FORTITUDE ALS. Our Q3 2019 R and D expenses decreased to $20,200,000 from $21,700,000 in the Q3 of 2018, primarily due to lower spending related to our neuromuscular development activities, offset by increased activities related to METEORIC HF and CK-two seventy four. More than half of our R and D expenses were attributable to our cardiovascular programs as expected given activity for METEORIC HF and the cardiac myosin inhibitor program and the remainder of our expenses were attributable primarily to our early research activities. Our Q3 2019 G and A expenses were $9,800,000 up from $7,200,000 in Q3 2018 due primarily to increased outside legal expenses and higher personnel related costs, including stock based compensation.
And now Qing will review our corporate development strategy.
Thanks, Robert. As Robert mentioned, we ended the Q3 with RMB 166 1,000,000 in cash, which represents nearly 24 months of formal cash based on our 2019 guidance of RMB 85,000,000 to RMB 90,000,000 net cash burn. As we have previously stated, our strategy remains to manage our cash prudently through the expected readout of results from GALACTIC HF in 2021. Toward that objective, in September, we presented our strategic plan to our Board, which focused on prioritizing near term spending to position the company for long term growth. Prior to the Board meeting, we engaged the company's middle management and senior leadership team in a program prioritization exercise, and then we did the same with our core members.
We consider scientific and clinical validation, probabilities of technical success, regulatory path to approval and market access and commercial potential. We also assess unmet patient needs and potential for impact. The results from all three groups were remarkably similar and echo what Robert outlined at the start of the call. We consider omni kevin carbol to be our top priority, CK-two seventy four in OHTM to be our 2nd priority and RADAV in ALS to be our 3rd priority. As such, near term spending will be allocated based on this range order.
What that also means is that others of our programs in development and research will not receive comparable funding until such time as we have access to more capital. For long term growth, we also discussed with the Board our approach to broaden our research platform and to strengthen our commercial capabilities in anticipation of potentially multiple commercial product launches in the next few years. As we look towards year end, our balance sheet remains strong, but we also are continuing to seek additional capital to extend our cash runway through a recent expansion of activity, inclusive of potential business development collaborations and or project financing. In the Q3, we made progress towards our potentially executing on multiple transactions, some of which we can foresee occurring in this current Q4. We remain confident in our ability to visually deploy capital against our prioritized programs to deliver optimal patient care and return on investment for our shareholders.
And with that, I'll turn the call back over to Robert. Thank you, Qing. To pick up on Qing's comments regarding prioritization of R and D programs and spending, the exercise we went through with our management team and Board was especially instructive. And based on conversations we've had with many of you, we believe our internal priorities are well aligned with feedback we've received from external stakeholders as well. As we execute on these priorities, we do so with an eye towards initiating commercialization of what could be our 1st approved therapy, omecamtiv mecarbil.
As you heard, we're substantially dialing up pre commercial activities, specifically in the areas of health, economic and outcomes research, market access and commercial planning. And we've added key new hires to our teams alongside those of counterparts at Amgen. The number of concurrent work streams in support of potential launch readiness is impressive and underscores the significant opportunity that omecamtiv mecarbil systolic dysfunction heart failure with a clinical and economic burden that's only growing given the aging demographics. I also want to emphasize our enthusiasm and urgency to initiate REDWOOD HCM, the Phase II clinical trial of CK-two seventy 4 in patients with obstructive HCM. This is a patient population in great need of novel therapies to treat both the symptoms of HCM, which impact everyday life and the ability to do some of the things that we take for granted like walking up a flight of stairs or going food shopping as well as the underlying contractile dysfunction in fibrosis.
As Fady discussed, the data from our Phase I study augured well for what we may see in the Phase 2 trial and ultimately what physicians can look forward to in terms of ease of use, titration and potential safety and efficacy in the clinical setting. Finally, we're continuing to delve deeply and critically to evaluate the results from our recent Phase II clinical trials of reldesemtiv in ALS and in SMA. In parallel, we're working with regulatory authorities and payers to assess various approaches we may consider to advance relesemtiv into later stage clinical development. Most recently, at the NEIL's meeting last month, Jeremy Shefner, the principal investigator for FORTITUDE ALS, presented additional post hoc analyses from a trial that showed faster progressing patients who received any dose of reldesemtiv experienced a statistically significant and clinically meaningful lesser decline in ALSFRS as measured from baseline to week 12, that did their counterparts who received placebo in addition and in both cases to standard of care. These results are important because if reldesemtiv can have a positive impact on faster progressing patients over just 12 weeks, it's reasonable to hypothesize that we may see an impact on function and disease progression for slower progressing patients over a longer time horizon, and thus we have a compelling opportunity to potentially demonstrate that a treatment benefit of the future clinical trial by either evaluating a broader set of patients to be studied over a longer time horizon or otherwise by enriching the trial with faster progressing patients.
But in both scenarios in order to show a potentially clinically meaningful and statistically valid therapeutic effect of reldesemtiv in patients with ALS. Towards that objective, we recently received some feedback from FDA in response to questions relating to a draft registration trial protocol and we're pleased to see the responses were constructive and supportive of our plans. Moreover, we're especially pleased that our plans seem to resonate with recently published FDA guidance pertaining to drug development in ALS. As previously mentioned, we can't anticipate beginning a Phase III trial until soonest the latter half of twenty twenty. And between now and then, we'll finalize the protocol, obtain additional investigator and regulatory feedback and operationalize the study plan before committing to do so.
We also need to restructure and clarify the economics and respective roles and responsibilities under our collaboration with Astellas. Towards that objective, we had previously communicated our want to renegotiate certain terms of our collaboration agreement. I'm pleased to report that we at Astellas have agreed in principle to revise the terms of our collaboration agreement so that Cytokinetics would have the exclusive right to develop and commercialize all fast skeletal troponin activators, including reldesemtiv and CK-six zero one. In that case, Astellas' future contributions would be to provide partial co funding for certain Phase III clinical trial costs for reldesemtiv in ALS and to provide other in kind support. And in exchange, Astellas would receive a low to mid single digit royalty on reldesemtiv to be payable by Cytokinetics.
We also agreed at the Principal to extend our joint research program for another year with Astellas sponsoring research cytokinetics through 2020. Of course, these agreements in principle are non binding and they're contingent upon our finalizing amendments to our collaboration agreement. And absent that agreement, the terms of the existing agreement remain in place. In the meantime, however, we continue to plan for the potential advancement of reldesemtiv into a Phase III trial again later in 2020. We also remain dedicated to advancing research, education, support and awareness for the patient populations we serve.
During the quarter, we announced the continuation of our partnership with CureSMA to increase education awareness, public policy and fundraising for spinal muscular atrophy. We're also very pleased to recently announce a call for proposals for the 2nd annual cytokinetics communications fellowship grant program, which provides grants to select patient advocacy group organizations that are serving the ALS heart failure, HCM or SMA communities. These grants would be intended to support increased capacity in communications, awareness building and community engagement, key activities we've identified again for advocacy organizations who are in need of support. Given that, now let me recap our expected milestones for the remainder of 2019. For omecamtiv mecarbil, we expect to continue to conduct the Lactic HF and METEORIC HF in patients with heart failure throughout 2019.
For CK-two seventy four, we expect to begin Redwood HCM, our planned Phase II clinical trial in patients with obstructive HCM in this Q4. For AMG 594, we expect Amgen will continue the Phase 1 study of AMG 594 throughout 2019. And for reldesemtiv, we'll continue to advance planning for potential future trials in ALS and SMA. For preclinical research, we expect to continue research activities under our joint research program with Astellas directed to the discovery of next generation skeletal muscle activators again throughout 2019. We also expect to continue our other muscle biology focused research, including the expansion of our research activities beyond the contractility of muscle to the energetics of muscle.
And operator, with that, we can now open up the call please to questions.
And we will take your first question from Jason Butler with JMP Securities.
Hi, Jason.
Hi. Thanks for taking the questions and congrats on all the progress across the pipeline in the quarter. I had a couple on 2 seventy four and then a follow-up on Omecamtiv. For the Phase 2 Redwood trial, Fady, I think you said that you're going to be assessing the LVOT gradient both at rest and post exercise. If that's correct, can you just talk about those two measures and how we should think about those data points and how informative each is in terms of Phase III planning?
And then can you just speak to how you think about opportunities for CT-two seventy four beyond obstructive HCM, for example, and those obviously in non obstructive patients?
Yes. Sure. I'll take the first question. So just to be clear, what we will be assessing is the effect of 274 on the left ventricular outflow gradient at rest and post Valsalva, not post exercise. So Valsalva is a breathing maneuver where you fare down against a closed glottis, so that you're generating into thoracic pressure and increasing the gradient through that means.
It's a common maneuver that's done in HCM patients to look at maximum gradient. And so those two maneuvers will look at both the Valsalva gradient and the resting gradient in this trial. There won't be an exercise assessment in this trial. I think our experience in other domains just really to be confident in a placebo controlled trial of the effect of any drug on exercise, we need a much larger study than we have planned right now for this safety trial. The second question you asked, if you can remind me what
Just wanted to know the impact of that to Phase 3 plan.
Right. So the relationship to Phase 3 planning is that the effect of CK-two seventy four on the gradient is the most sensitive way by which we can establish dose and a dosing regimen. It's a highly sensitive biomarker of cardiac myosinact inhibitors effect and it will enable us really to characterize exposure response relationship and set the dose properly for Phase 3. So that I think was the main objective of our Phase 2 study is to ensure that we are dosing patients that are similar to those that we would enroll in Phase 3 and then we dose them with a similar dosing regimen as we would employ in Phase 3. So Jason, you also asked about next steps that could include other indications.
And I think we're putting those on pause right now to better understand the landscape around which a cardiac myosin inhibitor may have effect in non obstructive HEM, but also in other indications where we have ambition. So as you heard our priorities laid out, those are certainly potential priorities down the road. But given our current capital and how we're thinking about our business right now, we're going to focus to those things that we underscored in this call.
Great. And then just one on Omecamtiv. Can you provide us any color around the upcoming interim in terms of whether the stopping boundaries are focused on the primary endpoint versus key secondary endpoints such as cardiovascular death? And then do you have any plans to present or publish baseline characteristics or the statistical analysis plan at any point? Thanks.
Yes. So I can't really comment on specifics of what the criteria are. Clearly, obviously, they would involve the primary endpoint being met, but I won't really comment beyond that. The baseline characteristics of the trial will be something that will come out in an appropriate academic forum in the next few months. And the we are planning to publish a paper on the design of Zolactic that will hopefully also be in the public domain in the next few months as well.
I think in many respects, having that information will elaborate on some of the things you've been asking about, Jason, and that will be forthcoming.
Great. I appreciate all of the additional details. Thanks again for taking questions.
Thank you. Thanks, Tate.
Your next question comes from the line of Joe Pantginis with H. C. Wainwright.
Hello, Joe.
Hey, guys. Good afternoon. Thanks for taking the questions. A couple of questions. Actually, it's nice to get the visibility on the Astellas collaboration for reldesemtiv and reaching almost the ultimate endpoint here of having these negotiations virtually complete.
So my first question is, I guess, they're somewhat related is, can you give any indication of the level of co funding that Astellas might provide for the Phase III? And also, I guess, it impacts what your the overall impact on milestone revenue is for the next 24 months?
Yes. So obviously, this is still a matter that is dynamic. And at this stage, we have agreement in principle, but there's still a number of other things that have to be agreed and finalized before we could really answer your question. But I think you should expect that were we to make a final agreement, this would be a program that Cytokinetics would be advancing where the majority of development costs non clinical and clinical would be borne by Cytokinetics and Astellas would provide co funding, but it would not be a majority, but rather a minority of that co funding and in exchange for royalty. The flip side of that is Cytokinetics would be retaining the exclusive commercial rights in order to enable a substantially bigger piece of the economics on the other side.
And with regard to milestones and royalties, I think that will have to stay silent for now. We'll not comment like we haven't before on what would be potential milestones and royalties, only that which is earned.
I understand. No, thanks for that. And then I guess the question is, is the drug or open for re partnering? Is this something you want to consider or wait until you have some finalized Phase III protocols? And then secondly, a question for Fady, maybe I just wanted to see if there was any update regarding METEORIC.
Thanks.
Yes. So I'll start and then turn it over to Fadi. Regarding partnering, the reason we approached Astellas the way we did is very much because we have conviction ourselves to be leading the development and commercialization of reldesemtiv in ALS and SMA. So I think partnering is not right now something that we're giving much thought to as much as we're rather instead trying to figure out how we ourselves want to go forward and with what kind of timing, protocol, budget, etcetera. And with respect to METEORIC, I'll turn it back to Fadi.
Yes. We're very pleased with how METEORIC is going. We've continued to add sites to the study regularly, sites enrolling well, the sites that are open that we have I think we're on track in terms of enrollment in that study. Types of patients we're getting, I'm very pleased to see sort of these are the kinds of patients I think we can have an impact on their exercise performance just based on the initial characteristics of their exercise testing. So, I'd say we've been storing smoothly there.
Great. Thanks a lot guys.
Thank you, Joe. Thanks, Brad.
Your next question comes from the line of Chad Messer with Needham and Company.
Hello, Chad.
Hello. Good evening and happy Halloween and thanks for taking my questions. First, I had one on the Neals data that those results make a lot of logical sense to me. Was that something you also looked at with reldesemtiv in any
way? So this is with reldesemtiv, those data
I met with tirasemtiv, my apologies.
Your question is, did we look at the effects of Tirasemta parsing slow progressors from faster progressors? I'll let Fady answer that question. But before he does, I'll say one of the things that prompted us to do this is increasingly momentum in the ALS community to look at slow progressors distinctly from faster progressors in clinical research in general. And as you may know, the FDA recently approved a drug called AZERAVONE that was studied in an all comers population and was demonstrated no effect in that first Phase III study, but then based on a post hoc analysis, identified a clinically meaningful effect in a group of faster progressing patients and then studied that group again in another Phase III trial, only 129 patients in that second Phase III trial sought a meaningful effect on ALSFRS at 6 months and submitted that for FDA approval, FDA approved it for all patients, faster and slower progressing patients. So that was remarkable and very important in informing the way we wanted to approach some of these analyses and some of our thinking.
And I'll now turn to Fady to answer your direct question. Yes. No, we did look at those sorts of things in the vitality study as well. And the I think our conclusions were very similar in that the slowest progressors benefit the least and they dilute the signal that you see with the faster progressors. And so it made sense that if you will having taken a look at it and afforded to do that we saw the same thing.
It stands to reason that if the therapeutic hypothesis for an investigational medicine is to slow the decline of disease progression, it's difficult to separate that potential effect out absent some measure of progression in a patient population. So it's in one way an enrichment strategy to enroll those patients who are faster progressing, but it's also a practical one.
That all makes sense to me. And you've kind of almost completely precluded my follow-up to that, which is whether looking at the faster progressors is what makes sense for your next trial. I don't know whether you'll comment any further on trial design. I know you're still working that out,
but that sounds like
a logical way to consider.
Here's what I'll tell you, Chad. There's still a lot of work we need to do in order to be able to make a commitment to a next trial. We mentioned that we did have a round of questions with FDA in a Type C meeting interaction, but we still want to have an end of Phase 2 meeting. There's still a whole bunch of work we want to do with our statisticians and with clinical opinion leaders. We not only want to talk to clinical experts and regulatory parties, but we're doing a very deep dive with payers, both in Europe and the U.
S. We want to understand what they perceive to be the more meaningful value drivers before we might commit to another tranche. So all of this is going to take some time and I think it's the right thing to do to be asking and answering these questions and we'll have more to say as we continue these activities. Great.
And then if we could just move on quickly to HCM. Can you maybe briefly educate me on what the important differences are between obstructive and non obstructive? At a clinical level, the patients look have a lot of similarities. So both you guys and MyoKardia have kind of prioritized the obstructive. I was wondering if there's anything trickier about the unobstructive ones, whether it's clinically or regulatorily or just a heterogeneity or something?
Any direction on that would be appreciated.
Thanks. Yes, certainly. So the HCM patients are classified to these 2 subtypes. And the reason for the class patient is that the obstructive patients, the muscle, the heart thickens asymmetrically. And it thickens to a greater extent right underneath where the blood exits the heart out of the aortic valve.
And so as the heart is contracting, that obstruction gets in the way with blood leaving the heart and therefore it's called destructive hypertrophic cardiomyopathy. In those patients relatively small changes in the way that that muscle functions can have big impacts on the outflow of blood from the heart because the obstruction the leak of the obstruction can greatly improve forward cardiac output. The non obstructive patients generally have thickening of the heart all around And maybe it may not be the same everywhere, maybe that asymmetrical, but it isn't right underneath where the outflow leads to heart. And in those patients, their symptoms are derived from how stiff the heart is. And so different factors are at play, if you will, in terms of relieving.
And you really need to probably see improvements in the way the heart fills, in the way the heart remodels. Potentially, it may take longer to see an impact of drug therapy in that population, whereas in the obstructive patient, you can achieve a relatively quick pharmacodynamic effect of relieving the obstruction and thereby including their symptoms on the basis of that. Okay.
So I guess given that we have an opportunity to learn a lot this quarter from the mavacamten Stage 2 study. Anything you are particularly hoping to learn from that?
Yes, absolutely. I mean, it will be very interesting to see how the non instructed patient will behave. I'm optimistic that they will find positive effects of the mechanism of action in that patient population and on their symptoms and potentially on their exercise tolerance as well.
All right, great. We'll certainly be paying attention to that and looking forward to you guys starting your own Phase 2 in obstructive. Thanks for taking my questions.
Thank you, Chad.
Your next question comes from the line of Jeff Hung with Morgan Stanley.
Good afternoon, Jeff.
Hi. This is Hannah on for Jeff. We had just a few more questions on FCT-two seventy four. So how long do you expect enrollment to take and when might we see initial data? And then given that the Phase I was in healthy volunteers, can you remind us what gives you confidence that we'll see the LVOT gradient improvements in the obstructive HCM patients?
Yes. So it's a little early to comment on how long we think the trial will last. We expect to see results in 2020 from some set of patients in that trial. We'll have more to say about it as the trial gets underway and begin enrolling in our upcoming quarterly call. As to your second question, the effect of CK-two seventy four in healthy volunteers was to reduce overall cardiac function.
And so it was clearly active in that population and that effect of reducing cardiac contractility is the basis for reducing the left ventricular outflow tract obstruction. So we fully expect the healthy non volunteer data to be predictive of what we will see in the patients. Yes. It's not just the Phase 1 data that lends support through that therapeutic hypothesis. It's also preclinical data that are very consistent for pharmacodynamic effects.
What I'll also say is with regard to timing of results, as Fady indicated, that depends on enrollment. It also depends on whether we're going to be dose escalating from 1 to 2 cohorts or 2 to 3 cohorts. That's ultimately going to be determined based on the data we're observing.
Great. And then if I can just ask one more on financials. How are you thinking about the cash burn in expenses? Are you still guiding to, I think it was 85 to 90,000,000 in cash burn?
That is correct. For 2019, we're still guiding to 85,000,000 to 99,000,000
Okay, great. Thank you.
Thank you.
Your last question comes from the line of Ted Tenthoff from Piper Jaffray.
Most of my questions have been answered, but I wanted to kind of get a sense for sort of the opportunity for 274 in different types the condition. So whether it be obstructive or an obstructive or non obstructive, how do you sort of see that progressing, if you could share? Thanks so much.
Yes. I'll start and maybe ask that to comment. We've been working in this field for quite a long time as pioneers as it pertains to both activating and inhibiting cardiac myosin. We've learned a lot pre clinically and clinically that reads across multiple different patient populations and we certainly understand this biology quite well. As such, we're looking at this development program as it pertains to addressing issues of hypercontractility, whether that manifests itself in patients with HCM, obstructive or non obstructive, but there are also other populations that have hypercontractility, as I'll ask Fady maybe to elaborate.
Yes. I think there are obviously the patients with HBM, the obstructive, non obstructive patients, there's also a large population of patients with heart failure with preserved ejection fraction. And I think we're learning more about those patients and how to sub pacify them. Certainly, there is going to be a substantial portion, I think, to the basis for their symptoms and their condition is underlying hypercontractibility of the heart. Often you see in these patients very high ejection fractions, hearts that have hypertrophy.
They may not have hypertrophy and increases in cardiac function of the degree that HCM patients do, but they're part of that continuum. They may also provide us an eventual opportunity to explore this mechanism in. You may have seen an article in The Wall Street Journal yesterday about heart failure and its increasing prevalence and clinical and economic burden. And that's not just systolic dysfunction heart failure. Increasingly, a cardiometabolic disease is reading on HFpEF and there are components and subsets of the HFpEF group that we're especially interested in.
And this is a very significant area of ongoing research and development at Cytokinetics. So it's premature to be speculating too much on that until we have more of a basis by which we can commit to shareholders as to what we would be expecting to do. But please know that it is an area of very high interest for us.
Makes a lot of sense. Appreciate the update. Have a good one, guys.
Thanks, Chad. Thanks, Chad.
And there are no further questions at this time.
Thank you, operator. And I want to say thank you and happy Halloween to everybody that joined on the call. I hope we didn't keep you too long. I will say that we shared quite a bit today about how we're thinking about priorities at the company and how we're thinking about extending and preserving capital through our most important value generating milestones. And I do believe that, as we've elaborated, we're aligned with feedback we've received externally from shareholders, but also as is in keeping with our reputation and history of following the science.
As such, we look forward to keeping you updated on our progress as we conclude 2019 and peer through 2020 and especially as we recognize there are quite significant value creating milestones anticipated as we go forward. With that, we'll end the call and thank everybody for their time and your interest in our company.
Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.