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MyoKardia, Inc. (MYOK)
Q4Â 2019 Earnings Call
Feb 27, 2020, 4:30 p.m. ET
Contents:
- Prepared Remarks
- Questions and Answers
- Call Participants
Prepared Remarks:
Operator
Ladies and gentlemen thank you for standing by and welcome to the MyoKardia Fourth Quarter and Full-Year 2019 Financial Results Conference Call. At this time, all participants in a listen-only mode. After the speaker presentation, there will be a question-and-answer session. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions]
I would now like to hand the conference over to your speaker today Michelle Corral. Please go ahead ma'am.
Michelle Corral -- Senior Director, Corporate Communications and Investor Relations
Thank you, Josh. Good afternoon and thank you for joining us on today's call. I'm Michelle Corral, MyoKardia's Executive Director of Corporate Communications and Investor Relations. Today, we will be reviewing fourth quarter and year-end financial results for 2019, as well as discussing recent progress and upcoming milestones across our portfolio. A press release detailing the financial results was issued earlier this afternoon and is available on our website. Leading today's call is MyoKardia's CEO, Tassos Gianakakos. Tassos is joined today by Dr. Jay Edelberg our SVP of Clinical Development; Bill Fairey, our Chief Commercial Officer; and Taylor Harris, our Chief Financial Officer.
Following their prepared remarks, we will open the lines for Q&A. As a reminder, the information discussed during this call will include forward-looking statements, which represent the Company's view as of today February 27, 2020. We undertake no obligation to update or revise any forward-looking statements to reflect new information or future events except as required by law.
Please refer to today's press release, as well as our filings with the SEC for information concerning risk factors that could cause actual results to differ materially from those expressed or implied by these statements.
I'd like to now hand the call over to our CEO. Tassos?
Tassos Gianakakos -- Chief Executive Officer
Thanks Michelle. Good afternoon and thanks for joining us today. Our Company is just a few months away from pivotal data, which we expect will enable us to file MyoKardia's first new drug application with the FDA. We're coming of a year that really highlighted the breadth of our science and our pipeline, which now includes candidates to potentially help people with obstructive HCM, non-obstructive HCM, specific forms of HFpEF, genetic DCM, and other forms of systolic heart failure.
Assuming continued success, we see MyoKardia assuring in the era of precision medicine broadly in cardio vascular disease management, enabling functional cures for many of the millions of people worldwide suffering from heart failure, changing their lives in ways we've witnessed in other precision disease areas. While we're incredibly excited about 2020 and the many significant milestones that lie ahead, keep in mind it's just the beginning of what our precision medicine strategy and translational research platform can achieve.
We continue to see more and more evidence supporting the broad value of our approach throughout the eight years since the Company's formation, which has resulted in three clinical programs, two pre-clinical programs, and multiple additional research stage programs, all home-grown and discovered by our MyoKardia scientists. This year you will continue to see this approach in action with both mavacamten and danicamtiv.
The next in a series of near-term proof points for mavacamten would be the release of the complete MAVERICK trial data, the largest and most comprehensive study, conducted to-date in non-obstructive HCM at the American College of Cardiology in Chicago in March. Results have been accepted for a late-breaker presentation and those data enable us to move mavacamten forward in non-obstructive HCM, which was the main purpose of this ground breaking study. In addition, the MAVERICK trial validated our hypothesis about mavacamten's potential to benefit people with certain types of diastolic heart failure. And not to be overlooked, MAVERICK further increased our confidence in the Phase 3 EXPLORER trial and obstructive HCM.
In the second quarter, we'll be sharing the top line results from EXPLORER, which we feel great about. Between now and then, we will be discussing the opportunity that we see in diastolic heart failure, often referred to as HFpEF and why we believe our approach to tackling this syndrome effecting millions of people to make a meaningful difference where no therapies have yet to be developed.
Around mid-year, we plan to present data from our Phase 2 study of danicamtiv, formerly known as MYK-491. The data from our danicamtiv program so far has been really encouraging, supporting our decision to initiate a Phase 2 study in people with genetically defined dilated cardiomyopathy. These genetic abnormalities contributing to the disease are estimated to present in about 30% to 40% of all DCM patients.
As with all our programs, including mavacamten, this study has been designed to both provide us with a robust signal of danicamtiv's mechanism, laying the foundation for an efficient development path in this targeted patient population, as well as gain insights on the impact at improving systolic function without the tracking from diastolic can have in a broader subset of DCM patients.
Today, we'll be focusing on mavacamten for HCM. Jay is here with me to review some of the key aspects of the EXPLORER study and upcoming readout. We're also joined by Bill Fairey, our Chief Commercial Officer who will share with you some of what we're learning about the burden of HCM and the gaps in the current treatment landscape and we'll also discuss our market development efforts.
Finally, Taylor will round out the call with a summary of our financial position and will recap many of the important anticipated 2020 milestones to come. Jay?
Jay Edelberg -- Senior Vice President, Clinical Development
Thank you, Tassos. Good afternoon to everyone.
Today, I'll touch on several key aspects of the Phase 3 EXPLORER study, namely dosing and safety, powering assumptions and the composite functional end point. EXPLORER is the largest and most comprehensive randomized clinical trial of obstructive hypertrophic cardiomyopathy conducted today with more than 70 sites across 13 countries, enrolling 251 patients with symptomatic obstructive HCM.
Let's start with the individualized dosing. From PIONEER and then OLE, we learned how to dose mavacamten in obstructive, HCM based on clinical response, namely reduction of left ventricular outflow tract gradient. When we dosed mavacamten to reduce LVOT gradient, we've observed improvement in multiple parameters, including NT-proBNP, filling pressures, and left atrial volume, all while left ventricular ejection fraction remained in a normal range.
In EXPLORER, patients start on a low dose of 5 milligrams of mavacamten and can be increased at two time points to further reduce the obstruction in LVOT if needed. Starting low and gradually increasing is how we expect mavacamten would be used in clinical practice.
Turning to the endpoint selection in powering. Our composite functional endpoint is designed to capture improvements in symptoms and cardiac function, using NYHA classification and measures of peak VO2. The composite functional endpoint is defined by achieving either an increase of peak VO2 of 1.5 milliliters per kilogram per minute or more and an improvement in NYHA class, greater than one -- one or more or an increase in peak VO2 of three or more and no worsening in NYHA class.
For this endpoint, EXPLORER is well-powered, greater than 95% to detect the 25-point delta between active and placebo. Our powering assumptions are based on a 50% treatment response rate. We derived our assumptions for the placebo response rate of 25%, after looking at other studies that incorporated measures of symptoms and function, notably the Gilead LIBERTY Study.
In addition, the placebo response observed in MAVERICK when applying the composite functional endpoint was 21%, adding to our confidence in our estimates for the anticipated placebo response in EXPLORER. EXPLORER was designed with assumption for up to 15% discontinuation. Without sharing specifics, I can say that we are well below that range. Patients in EXPLORER are staying in the study with a great majority joining the long-term extension study. In addition, EXPLORER enrollment surpassed our target of 220, adding further power to the trial. Throughout EXPLORER, the IDMC is met on a quarterly basis, and we have received the green light with each review. In EXPLORER, we will look at several key efficacy measures beyond the composite functional endpoint. We expect to see a reduction in gradient. Our base case is to achieve statistical significance versus placebo. We feel really good about the clinical impact of mavacamten. We hope to see a meaningful reduction in gradient in the majority of patients.
From PIONEER and studies of myectomies, we know that reductions in LVOT obstruction lead to improvements in symptoms. We want to see NYHA classification improve in this double-blind placebo-controlled setting. In our open-label single arm studies PIONEER and PIONEER-OLE, mavacamten treatment resulted marked changes in NYHA class with 70% to 80% of patients improving by one class.
In the placebo-controlled EXPLORER trial, we believe in an improvement in NYHA class in majority of patients on treatment will be meaningful. Finally, we will look at peak VO2, a measure of cardiac function. Cardiopulmonary exercise testing is the most rigorous standard by which we can measure improvements in the heart's function and we'll look for improvements in peak VO2 with treatment versus placebo.
As we readout the results of EXPLORER, we believe that these three parameters along with the drug safety will be the most critical and we are highly encouraged that we've observed improvements in all these areas in our studies of mavacamten today, as well as several other biomarkers of improved heart health. All EXPLORER patients are now through the dose adjustment period. So, in the home stretch, we remain on track to report top line data in Q2. Our top line readout will be based on the data gathered through week 30. At the top line data readout, we anticipate reporting on the primary composite functional endpoint and secondary endpoints of NYHA classification, peak VO2, and LVOT gradient, as well as safety and tolerability.
EXPLORER is the key study in our comprehensive registration program. Data from all our studies with mavacamten will be part of the submission, including our long-term extension study known as MAVA-LTE that will increase our safety database. Supplement to our anticipated filings will be the valor HCM trial, which is our study starting in Q2 in patients we're being evaluated for subtle reduction therapy.
We've partnered with the Cleveland clinic in many other top-notch surgical centers to see if mavacamten treatment they provide an alternative to invasive procedures for these patients.
I'd like to now turn to the line over to Bill Fairey, our Chief Commercial Officer. Bill?
William Fairey -- Executive Vice President, Chief Commercial Officer
Thanks Jay. Just to pick up for a moment on something Jay was just saying, one of the things that makes my job a bit easier is that our mavacamten program is set up to provide the evidence we need for a successful launch. When we ask cardiologists about the product attributes that matter most, what we've learned is that the EXPLORER trial design addresses a number of them.
For example, at the top of their list, just behind our mortality benefit is an improvement of NYHA class or improvement of symptoms and increase in exercise capacity as measured by peak VO2 and reduction in left ventricular outflow tract gradient are also highly valued product attributes. So, sitting where we are right now, we feel quite good about the dataset EXPLORER should deliver.
I might also add that our VALOR study, which will evaluate mavacamten as an alternative to subtle reduction therapy, should provide additional evidence that mavacamten can address another serious aspect of the disease, that being the avoidance of reduced need for SRT and this is clearly valued by cardiologists. As we look ahead, toward what we anticipate will be a positive readout for EXPLORER, there's a tremendous amount of work that's been ongoing to understand and develop the HCM market.
What we've determined is that this is a disease category that has been underserved for a long time, due to the limitations of current therapies and that there is an express need for targeted therapeutic options. The commercial and medical affairs teams are planning for success and we are currently laying the groundwork for an eventual market introduction of mavacamten for obstructive HCM.
We're building a very capable team with significant experience in rare and specialty disease areas. And so far, we've brought on board heads of marketing, market access, commercial operations, advocacy, field medical, real world evidence and health economics. Now, one aspect of our work has been to better understand the burden of disease on patients and their families and the more we talk as representatives of the HCM community, the better we understand the profound impact HCM has on patients' lives.
So, what is life like for patients with HCM? Well, we know it's a chronic progressive and typically inherent condition and while there are various estimates for HCM's prevalence, the most reliable epidemiology study cite one in every 500 people worldwide are affected by HCM. Today we think there are about 100,000 patients diagnosed and treated here in the US, which is roughly 15% to 20% of overall prevalence and two thirds of these 100,000 have the obstructive form of the disease, while the remaining one-third are non-obstructive. Fatigue, shortness of breath, palpitation, exercise intolerance and/or chest pain are all symptoms of the condition.
The onset of symptoms can be settled and can be confused with other owners such as asthma. As a consequence, HCM is underdiagnosed. In fact, it can take multiple years for a patient to be correctly identified as having the condition. And the way HCM presents may be quite different from person to person, even among patients with the known underlying mutations, the course of their disease can be highly varied. We've met patients families with dozens of members who share the same pathogenic mutation where one sibling may tragically die of sudden cardiac arrest at a young age and another will need a heart transplant into their 40s and yet still another sibling won't develop any symptoms until very late in life, all from the same family.
The disease burden can be significant. HCM patients have a three time higher mortality rate when compared to that of the general US population at similar ages. And while relatively rare, sudden cardiac death is a very real risk associated with the condition. The patients have told us that there are many days where they can't walk down a city block without resting. One patient said that they won't even try to walk on a beach any longer. Some days, they say it is like an elephant sitting on her chest. They avoid the subway because of the stairs and one patient lamented that her shortness of breath is so severe now that they can no longer sing. And the list goes on. They are forced to scale back basic activities of daily living to accommodate their disease. Sometimes it's so gradually that they are not even cautious of the measures that they are taking. This is common practice. So, these patients are sick, some very sick and we know that current therapies will help for some, are not adequate for many.
Now, I'd like to shift gears and share some of what we know about who's treating these patients. We believe that the vast majority of the diagnosed patient population are under the care of a cardiologist. Our analysis of claims data suggests that roughly 75% of these patients are managed by community cardiologists and approximately 25% are managed by designated HCM centers or heart failure centers here in US and we think there is probably around 60 of those in total.
When way we look at this another way, we believe that 80% of the diagnosed patients are seen by 10,000 cardiologists, and 50% of these patients are seen by approximately 2,800 cardiologists. So, this is a relatively concentrated manageable physician universe for us to address.
I'd like to conclude my remarks by sharing a bit more on how we're preparing for launch. Our clinical scientists and field base medical liaisons are establishing meaningful relationships with the cardiology community. Herein, it should drive conversations around the mechanism of disease. The underlying pathogenesis of HCM and the need for new treatment options in the face of the inaccessible compromises required by some patients today.
Over the coming months, our goal is to continue to elevate these conversations and broaden our reach across the community to include a wider population of HCP's patients and payers. Additionally, we have enhanced our disease education efforts. We debuted the exposed HCM disease awareness campaign at AHA last November and we're releasing and accompanying online resource for physicians this spring.
It's also worth mentioning that our real world evidence team have kicked off a series of studies examining the burden of illness, HCM national history, and associated risk factors, as well as evaluation of associated clinical and economic values. We're partnering with large professional organizations to create custom impactful initiatives to further engage the community in a dialogue about the very real burden of life with HCM.
Recently, we kicked off a formal three-year campaign in partnership with AHA designed to heighten awareness and clarify some misconceptions about HCM among cardiologists, patients and their families. These new initiatives complement our other long-standing contribution to the HCM community such as the SHaRe registry, the development of the HCM Care App with Duke and our partnership with 23andMe.
Our commitment is to continue to drive education, awareness, and engagement around HCM up to and throughout a potential launch. I look forward to periodically providing updates on what we're learning and how we're developing the HCM market and our approach to the commercialization in mavacamten and the lead up to our anticipated launch.
I'd now like to hand it over to Taylor, who's going to walk us through the quarter's results. Taylor?
Taylor Harris -- Chief Financial Officer
Thanks, Bill. 2019 was a year of tremendous progress for MyoKardia with six clinical trials ongoing and significant growth in our infrastructure to support these development programs, as well as our pre-commercial preparatory activities. So, on a full-year basis, total operating expenses in 2019 excluding the $80 million repurchase of royalty rights from Sanofi were $208 million. That's compared to $107 million in 2018. Of that, R&D expenses for 2019 totaled $146 million and G&A expense was $62 million.
The uptick in 2019 expenses reflected increased R&D spending related to the advancement of mavacamten, danicamtiv, MYK-224 and our preclinical programs, as well as an increase in personnel and related costs. As of December 31, 2019, we had $430 million in cash and investments.
So, we enter 2020 fully funded to execute on all of our planned operational activities to the middle part of 2021, more than a year past the expected top line data readout for EXPLORER. Included in this runway projection is the full registration program for mavacamten in obstructive HCM and the ability to aggressively advance our mavacamten franchise in diseases of diastolic dysfunction, as well as our plans to bring danicamtiv and MYK-224 to the next stages of development, assuming encouraging data and to advance at least one of our emerging preclinical programs to an IND filing.
In 2020, we will have a number of milestones reflecting progress against our operational objectives. In just the first half of the year, you can expect MAVERICK data to be presented at ACC, the top line EXPLORER readout for mavacamten in obstructive HCM, a regulatory update and go-forward plans for mavacamten in non-obstructive HCM, the initiation of our VALOR HCM study looking at mavacamten as an alternative to settle reduction therapy, initiation of a proof-of-concept study of mavacamten in a targeted HFpEF population and than for danicamtiv the presentation of full Phase 2a data and the initiation of a Phase 2 study in genetic DCM.
Our momentum should continue moving into the second half of the year with data at both ESC and AHA including the full presentation of our Phase 3 EXPLORER results, top line data from our Phase 1 study of MYK-224, and the initiation of the MYK-224 Phase 2 study. And in the background we will be hard at work on our anticipated NDA filing, advancing our disease awareness campaign, building our US commercial infrastructure, exploring rest of the world commercialization opportunities, and advancing our research pipeline.
So, taken together, we expect 2020 to be a transformational year for MyoKardia. Putting us on track for our first commercial launch, while at the same time broadening our pipeline into multiple exciting arenas, all this in line with our precision medicine approach.
With that, I would now like to open the call up to your questions. As a reminder, here with me and Tassos are Dr. Jay Edelberg, and Bill Fairey.
Questions and Answers:
Operator
Thank you. [Operator Instructions] Our first question comes from Anupam Rama with JP Morgan. You may proceed with your question.
Anupam Rama -- JPMorgan -- Analyst
Hi, guys. Thanks so much for taking the question. On MAVERICK HCM ACC later next month, wondering what level of detail we're going to be getting on sort of drug concentrations of mavacamten, both on the efficacy side and then potentially safety inside that we might be able to get from that type of data? Thanks so much.
Tassos Gianakakos -- Chief Executive Officer
So, we're going to be presenting the comprehensive clinical data. The safety, the efficacy and we'll be looking primarily at biomarkers and also giving the details on the subgroup analysis that we've found the greatest response in there and to provide the correlations that give us our path forward in both the nHCM population, as well as the reason to believe in the diastolic dysfunction that have subpopulation that we think we could treat.
Anupam Rama -- JPMorgan -- Analyst
Okay. Thanks for taking my question.
Taylor Harris -- Chief Financial Officer
Thanks Anupam.
Operator
Thank you. Our next question comes from Tazeen Ahmad with Bank of America. You may proceed with your question.
Tazeen Ahmad -- Bank of America -- Analyst
Hi, good afternoon guys. Thanks for taking my question. Maybe just to refer to part of your prepared statement, you said that all patients have now completed the dose adjustment periods so that being locked in, can you provide a little bit more clarity on how long it would then take to clean up the data and to report top line?
Taylor Harris -- Chief Financial Officer
Hey, Tazeen. This is Taylor. So, we are right on track where we expected to be. We're expecting just for the data cleaning process, that could take up to 12 weeks and that's what creates the range that we think lands us in the second quarter. We're totally comfortable with the second quarter, but we're not going to pinpoint any more than that just because of the nature of that process.
Tazeen Ahmad -- Bank of America -- Analyst
Okay. Fair enough. Can you just clarify what preclinical talk work have been done or needs to be done that's going to allow you to file pending the positive data results upcoming?
Tassos Gianakakos -- Chief Executive Officer
All the preclinical work has been completed or is -- and is being -- will be part of this mission. So, that is nothing that is rate limiting.
Tazeen Ahmad -- Bank of America -- Analyst
Okay. Thank you.
Operator
Thank you. Our next question comes from Alethia Young with Cantor Fitzgerald. You may proceed with your question.
Alethia Young -- Cantor Fitzgerald -- Analyst
Hey, guys, thanks for taking my question. I just want to talk a little bit about how to think about ejection fraction, kind of heading into this readout obviously there is measured ways these for safety, but are there any other points of interpretation. And then, just maybe a commercial one, how do you guys think about kind of getting the population to figure the claims population a 100,000, that 500,000 where some strategies that you're deploying there? Thanks.
Tassos Gianakakos -- Chief Executive Officer
So, related to the ejection fraction. So, the EXPLORER program is based on clinical-based parameters whereas our Phase 2 data was using basically only dose ranging. So, with this, we're able to dose adjust and are able to avoid any significant drops in EF. Our patients could actually have a dosing holiday in the case if their EFs dropped below 50%, and then they are able to get back on the drug to finish the trial. So far all of our numbers indicate that this is working out well.
Taylor Harris -- Chief Financial Officer
Alethia just to check on a little bit, I think a way to think about EF going forward is really to look at periods of prolonged depression, unnatural depression of EF that might lead to heart failure. This is something that we feel really confident we can avoid both in the construct of a clinical trial for sure, but also in the real world where if you look at the open-label extension data, once we get patients to the right dose, they do really, really well. You have a stable sort of EF, you've got really consistent and stable efficacy and we've got now that confidence in our ability to dose in that manner from the open-label extension.
So, we're feeling great about where we are on that front with EXPLORER. So, for EXPLORER specifically, the things to keep your eye on as it relates to EF, is really kind of tolerability of mavacamten that might lead to heart failure. We got around that. The clinical communities got their eye on that and that I think is the important consequence from a safety standpoint of EF.
From an efficacy standpoint, I mean, really what we're looking at is getting rid of the obstruction in a way that essentially maintains EF in a normal range, increasing stroke volume, improving symptoms, lowering filling pressures etc. and we shall capture that in the composite endpoint in New York Heart and peak VO2. For the MAVERICK in the non-obstructive population, what MAVERICK really did for us is, it gave us the ability to tune in the dosing in very much the same way.
So, now we have got a lot of confidence coming out of MAVERICK that we can dose the non-obstructive patients safely up to their target, knowing where that target is for any individual patient in a way that will drive what we believe now to be the optimal benefit and that's going to be a big component now the next study is great. We've got that set up. Now, let's go on and prove that that dosing approach is really going to improve symptoms and improve function in patients.
I'm going to let Bill, if you remember, Bill, the second part of the question.
William Fairey -- Executive Vice President, Chief Commercial Officer
It's a great question. So, I think the first point is not to overlook that there are roughly 70,000 patients that are diagnosed and treated with the disease today. Many of them we believe are suboptimal. So, I think for the first couple of years of launch we've got our hands full with a tremendous opportunity. Now, starting now and throughout the launch phase there is going to be a big effort in growing the market, which is where you're getting at, right?
How do we increase diagnosis of this population and get them into their proper channels. There are some things we're doing now and there are some things we're planning to do. So, we launched this deceased state campaign which is really focused now on increasing awareness. We're going live with the website linked to the deceased state campaign at the end of March, which will help again, I think improve physician awareness around disease and help improve diagnosis.
Once we get, we've got this partnership with AHA. So, we're in a position now, I think, to promulgate information with the AHA out to their entire followership around HCM. This is a HCM-focused initiative with them, and then there are some kind of the more fundamental things that we will be doing as we get closer to launch.
I mean, we are going to invest heavily in CME, we are going to invest heavily in medical education and speaker programs and bring the KOLs and experts out to the community to help increase awareness and diagnosis and we are going to be working with the community to refer and get these patients for whom they suspect HCM may be the cause if you get them into a center quickly. So, there is a whole bunch of things that we're going to be doing to increase diagnosis. Hope that answers your question?
Alethia Young -- Cantor Fitzgerald -- Analyst
Thank you.
Operator
Thank you. Your next question comes from Ritu Baral with Cowen. You may proceed with your question.
Ritu Baral -- Cowen -- Analyst
Good afternoon guys. Thanks for taking the question. I'm going to focus my first question on your placebo-controlled -- I am sorry, your expectations for placebo group for EXPLORER. You mentioned that using the composite criteria, the placebo group and MAVERICK had a 21% of them had a response and that you also based -- you base this off of the Gilead LIBERTY Study. Can you talk a little bit to the demographics of the placebo groups and how that's comparing and shaping up to the demographics of the placebo group in EXPLORER. Is there a reason that you think that the placebo response will be higher in -- I am sorry, in obstructive patients versus the MAVERICK non-obstructive patients like how should we think about that? And then I've got a follow up for Bill.
Tassos Gianakakos -- Chief Executive Officer
So, we estimated this originally off of the Gilead study, which was a combination of obstructive non-obstructive and that we estimated at 25%. We used our own data with MAVERICK and we found that it was 21%, so that made us feel very good. The question specifically about the demographics, the patients in MAVERICK looked demographically very, very similar to those who enrolled first in PIONEER and then in EXPLORER except of course the patients of the MAVERICK trial did not have a obstruction. That was the only difference in those. So, based on all of that, they told us that our Placebo assumptions were basically valid based on our ability to conduct a placebo controlled clinical trial, so we're pleased about this.
Ritu Baral -- Cowen -- Analyst
And then a commercial question on the different endpoints that go into the composite. I think you listed the -- you ranked ordered sort of the secondary endpoints and it sounded like it was in order of importance you listed in your Heart Association, then peak VO2 and then gradient. From a commercial perspective, is there some sort of meaningful threshold that you need to move the needle on NYHA in order to make the best -- in order to put your best commercial foot forward?
Tassos Gianakakos -- Chief Executive Officer
Well, I think showing class improvement is what the community was going to be looking for. I mean, can we move the needle in NYHA, and I think moving one classification is fantastic. So, not easily accomplished. And these patients as you heard earlier have a pretty significant burden of disease and a lot of it is limiting in terms of the way they conduct themselves in daily activities and quality of life, and it all comes down to -- a lot of it comes down to symptoms and ability to exercise. So, I think if we're able to demonstrate improvement in functional class, we are providing the community with something they've been looking for a long time and the quantitative research that we've done supports that.
Ritu Baral -- Cowen -- Analyst
You need to show like a certain percentage of patients need to actually hit the NYHA improvements versus peak VO2, I guess I'm wondering like if the composite is more one side versus the other side, does one profile present a much more commercially compelling proposition in the real world?
Tassos Gianakakos -- Chief Executive Officer
I think both sides, if we can think about from both sides are pretty compelling. You know, the combined endpoint addresses the NYHA component and also the peak VO2, which is a very objective measurement of cardiac function. So, I think both are values. I think that, if you -- and really I mean, we don't have much more to say on that. If I look at the attributes list, peak VO2 is just behind NYHA. So I guess it would depend on who you ask.
Ritu Baral -- Cowen -- Analyst
Okay. Got it. And -- go ahead, sorry.
Marc Semigran -- Senior Vice President, Medical Sciences
So, where you can think about peak VO2 is your maximum output, that's your real sprinting capability. We know patients are limited by that. NYHA is more of an integrated. How are you doing in your activities of daily living? These are both very important to me as a cardiologist. These are very important to my patients and being able to improve either is important. And so for some patients, one will be more important than the other, but both will be very meaningful to the cardiology community.
Ritu Baral -- Cowen -- Analyst
Got it. Thanks, Marc. And one quick last question. What are you guys thinking right now in terms of the commercial force to maybe hit those 2,800 low-hanging fruit cardiac traders -- cardiologist traders?
Tassos Gianakakos -- Chief Executive Officer
Yes. I think what we've talked about is thinking of a sales force size somewhere around 100, plus or minus, 20 or so. The plan is not to go after just the 2,800 at launch, the plan is to go broader than that to really kind of optimize, if you will, the opportunity. And going beyond that doesn't put enormous stress or strain on the organization, something we can manage, I think, pretty easily with those types of numbers.
Ritu Baral -- Cowen -- Analyst
Great. Thanks for taking all the questions.
Operator
Thank you. Our next question comes from Martin Auster with Credit Suisse. You may proceed with your question.
Mark Connolly -- Credit Suisse -- Analyst
Hi, everyone. This is Mark on for Marty. Thanks for taking my question. I guess, I was curious, how should we interpret the ejection fraction drops in PIONEER in the context of stroke volume? So in other words, to what extent was improved diastolic function able to compensate for the drops in ejection fraction? And then second, did you observe any correlation between ejection fraction and diastolic function in the study? Thank you.
Tassos Gianakakos -- Chief Executive Officer
Hey, Mark, I guess, going back to PIONEER, PIONEER was a dose-ranging study. So, just keeping that in context, the point of that study was to learn how to dose. And what we learned is that, we needed far less drug than we had anticipated coming into this study, so much lower doses, which is what you see now and explore. So the reductions of ejection fraction that were, let's say, more than just a few percent were driven by the dosing exploration that we did in the Phase 2. Flash forward to today where we have over a year and actually, 18 months plus in many of the open label extension studies, we're not seeing a whole lot of change in ejection fraction now that we've essentially determined the right way to dose these patients to both maintain safety, which is starting low and kind of increasing the dose only when necessary based on a clinical parameter, which is really important. And then once we get there, we optimize efficacy by not overexposing mavacamten to reduce EF unnecessarily. Difference there is, the reduction in EF unnecessarily isn't necessarily a safety concern, but it's not really adding a lot from our point of view to the efficacy.
So to optimize efficacy, if you will, we want to make sure that we are minimizing the reduction to EF. And these folks are still above the normal range, as you see in the open label extension, they're in the high 60s. So, I think that's a really cool thing that we're able to do with this drug that allows us to use clinical parameters that are connected, predicted to the outcomes that really matter to manage safety and optimize efficacy.
So, even for those patients in PIONEER that had, let's say a more than optimal reduction in ejection fraction, they still did better than their baseline. So, keep that in mind, right, peak VO2 improved, New York Heart Association improved and that's all good stuff. So, the only analog I will say is, MAVERICK gave us the same level of insights and information. So, we now have the ability based on a clinical parameter to adjust dose and get folks to where we think they're going to have their optimal benefit, while managing safety and tolerability on their way to their optimal dose.
Mark Connolly -- Credit Suisse -- Analyst
Got it. Thank you.
Operator
Thank you. Our next question comes from Etzer Darout with Guggenheim. You may proceed with your question.
Etzer Darout -- Guggenheim -- Analyst
Great. Thanks for taking the question. I just had a quick follow-up to the ejection fraction question. There seems to still be some confusion as to what the safety data we could get on the EXPLORER topline, and wondered if you could speak on that? And then second question, on the VALOR study, wondered if you could talk about the type of patients in terms of HCM severity, likely to enroll in this trial, as it compares to the types of patients recruiting into EXPLORER? Thanks.
Tassos Gianakakos -- Chief Executive Officer
Hi, Etzer, on the EXPLORER question and Jay will take the VALOR question. I don't -- we haven't given a lot of details on the safety data that will present for EXPLORER at topline. I think you should expect us to provide customary top line safety data at that point. We're going to have all of it, right, when we get into the medical presentation, but for us, the key things as it relates to safety that has to do with ejection fraction is really understanding the tolerability of the drug. And the -- if there's a persistent depression of ejection fraction below normal, in our clinical trials and both of our -- in all of our clinical trials, the protocols set a point at which it triggers some activity. That point, we picked for EXPLORER is 50%; in MAVERICK, we picked 45%, two different studies in different situations. So that is just a protocol-derived clinical threshold for things to happen in a clinical trial.
Transient excursions below 50 will happen -- they will happen to folks without HCM. In and of themselves, they are not a safety concern. So for us, putting those reductions in the app into the context of tolerability, particularly the most important would be, if you had people on mavacamten for several weeks, with an ejection fraction that is below 40, you would expect then the heart to start behaving differently. It would react, it would activate neural hormones that end up dilating the heart and saying, I've got to do something different here, because I'm not able to get enough blood to the rest of the heart. In this case, due to the fact that ejection fraction is being depressed.
So that is really the central thing to look at. It's been a very, very useful biomarker for us, both on the safety and efficacy side up until this point, because it does link to -- loosely links to contractility and the drugs activity. So, it's an important thing for us, but really now putting it in the context of safety, it's about tolerability and potential adverse events related to heart failure. I hope that helps.
Etzer Darout -- Guggenheim -- Analyst
Yes, thank you.
Jay Edelberg -- Senior Vice President, Clinical Development
And for VALOR, VALOR complements what we're doing in EXPLORER. It allows us to study patients now in the Class IV. So to all symptomatic HCM patients, patients on combination therapy who've completely exhausted their medical options, and now are seeking out an invasive procedure, either septal reduction therapy by an open heart myectomy or an alcohol septal ablation. And so these data we think will really provide additional evidence to the impact of mavacamten to provide important clinical benefits for our patients.
Etzer Darout -- Guggenheim -- Analyst
Great. Thank you.
Operator
Thank you. Our next question comes from Jeff Hung with Morgan Stanley. You may proceed with your question.
Hannah Lynne -- Morgan Stanley -- Analyst
Hi, this is Hannah on for Jeff. Thank you for taking our questions. Can you remind us how you're thinking about 224 and potential advantages it has over mavacamten? And then any aspects you'd highlight beyond the shorter half life? And then what are the gating factors to deciding if you'd partner in Europe? Thanks.
Tassos Gianakakos -- Chief Executive Officer
Okay. On the partnering in Europe side, I'll give you a high-level view on that, but let me start with 224. So, 224, when we started thinking about 224 as part of our strategy, we are a disease-focused company, we're not asset-driven', we are looking in the medium to long-term to optimally manage people who have HCM diagnose early, get folks into optimal care and really strive to get to a place where we're not losing anyone to this disease. That's our goal.
One new tool that we hope to introduce to the community to manage the disease is mavacamten, another one maybe 224. In the early days, so expect us to continue to research, in other words, HCM, broadly to make sure that we are meeting our overall objective here. So, more pipeline and more investment and research on that.
In the days before we got to the PIONEER result and certainly, the open label extension result with mavacamten, we were not entirely sure whether there was going to be an advantage or a disadvantage to having a longer half life drug. Mavacamten's is around seven or eight days or so. So, a good drug development that's focused on the strategy I just articulated, we started to discover other molecules. 224 was one where it has a similar activity profile, but has a shorter half life, also is metabolized a little bit differently that could provide differential potential benefits. Sitting here today, mavacamten looks really, really good. In fact, a long half life to us, it looks to be potentially an advantage, very stable PK. Once you get to your right dose, you are doing really well. And so it's unclear to us whether a shorter half life drug in and of itself would have a meaningful clinical differentiation or benefit.
There are some other aspects to 224, as we get the data, as Taylor mentioned, in the second-half of the year, we'll be able to speak more directly to this. That could make it more appropriate for different patient populations in different ways. We'll have to get the data to see. But for now, we're really liking what we're seeing with mavacamten. And if it does turn out that a profile of a drug like 224 has some advantages in certain situations, where we're right in a position to really be able to take that forward.
Hannah Lynne -- Morgan Stanley -- Analyst
Great. Thanks.
Tassos Gianakakos -- Chief Executive Officer
So, Europe, we're not in any particular rush to partner in Europe. We've got the expertise within the company to understand how to get the right development program and registrational package to support Europe. We also have, with Bill on Board and his team, we've got some folks in Europe and ahead of our European kind of market now in place, really learning at the local level and regional level about the opportunity for MyoKardia. So, we'll be in a position to really assess, whether we're the right company to take this forward on our own, or whether through a partnership, we might be able to provide more benefits to more people with HCM more broadly, more quickly. That would be the real driver for us. It wouldn't really be a financial driver per se, but really someone to help us achieve that mission and that strategy more effectively.
So, as we learn more about the market, we'll be able to assess the inbound interest, which we do get from potential partners with what it would look like for us to do it and who might achieve that mission more effectively. I will say that EXPLORER was a European and US study that we are understanding through our experiences with EXPLORER how patients are managed, treated and flowed in Europe. So, we've got a lot of experience on that and now already within the company.
Hannah Lynne -- Morgan Stanley -- Analyst
Great. Thank you so much.
Operator
Thank you.
[Operator Instructions]
Our next question comes from Mohit Bansal with Citi. You may proceed with your question.
Keith Tapper -- Citi -- Analyst
Good afternoon, guys. This is Keith on for Mohit. Thanks for taking our questions. The first one is from VALOR. Could you characterize the risk benefit profile you're seeing? Are you're looking for in order to supplant SRT and what's the bar there, I guess, other than non-inferiority? And then on 491 in the Phase 2a, just wanted to get a sense of how you're treating placebo effect, given stable disease there? And if there's any implication for Phase 2 trial design or endpoint? Thank you.
Jay Edelberg -- Senior Vice President, Clinical Development
So, for VALOR, we're looking to treat patients prior to a surgical or interventional procedure rather than to do a comparison. So, we'll be obviously announcing the specifics of the trial design when we get started, but we won't be going head-to-head against surgery, but giving patients the option of being able to avoid the need toward a procedure overall. And we think that based on the parameters that we have seen out of PIONEER, what we expect out of EXPLORER, we would think that this will benefit the vast majority of patients who are being considered.
Tassos Gianakakos -- Chief Executive Officer
And I want to make sure I understand your 491 question. Do you mind, sort of giving us another shot at it?
Keith Tapper -- Citi -- Analyst
Sure. So the Phase 2a looks like what's done in patients with stable heart failure. Just wanted to get a sense of how you're looking at placebo effect, given the stable disease and change over time?
Tassos Gianakakos -- Chief Executive Officer
Oh, sure. Yes. So, I think in a Phase 2a study and, Jay, feel free to chime in here and add. The placebo group gives you a lot of useful information around understanding tolerability and safety first and foremost in a lot of these early studies, and making sure that we can kind of better isolate treatment effect. Small numbers, right in these early studies, we've got tens of patients here. But that really is useful when we look to understand the signal strength that we're seeing on a variety of different symptom, echocardiographic, other biomarker-based readouts. So, with that in mind, it just gives us a lot more confidence and comfort that the signals and the trends that we're seeing are real and that we're starting to get a feel for during this period in time differences and tolerability.
Keith Tapper -- Citi -- Analyst
That's great. Thank you.
Operator
Thank you. Our next question comes from George Farmer with BMO. You may proceed with your question.
Gobind Singh -- BMO -- Analyst
Hi. This is Gobind on for George. Good afternoon, everyone. Thanks for taking the question. The first one, I guess is maybe a follow-up from some of our colleagues Anupam, I think and Alethia may have asked this and sort of combining the questions, but for the upcoming MAVERICK presentations, will there be any data on mavacamten concentration presented at that? And will there be any data on ejection fraction, given the MAVERICK trial was targeting those two different concentrations? And just wanted to see what kind of follow-up we'll get there?
And then my follow-up question was on the EXPLORER trial with the placebo response, so the 25%, I think, was from LIBERTY. And I think it was mentioned by Jay that 21% was the internal that you guys were seeing? Is this looking at the primary endpoint, because of composite? Or are we looking more at the 1.5, improvement, peak VO2 with improvement in NYHA. My understanding was, I haven't seen the NYHA data from LIBERTY trials. So, the second part of the primary endpoint, where there's no worsening in NYHA? It may have been presented and we just missed it, but I just wanted to see if you guys could help understand that part of it? Thanks.
Tassos Gianakakos -- Chief Executive Officer
Hi Gobind, I can hit the second one pretty quickly. It is a composite endpoint that drove the determination of the placebo effects. So, for MAVERICK, it's the same composite. For LIBERTY, while they didn't collect New York Heart Association, they collected Kansas City Cardiomyopathy, other quality of life measurements, which allow us to kind of get triangulate around something very similar. And so we made some conservative estimates around that. But in both cases really, the peak VO2 is what's driving the placebo response in either kind of form of the definition of a composite primary endpoint.
So very valid to look at both of those studies as appropriate analogs giving us confidence in EXPLORER. On the EF and MAVERICK, yes, so we were going to talk about EF, for sure. And in fact, the EF, the five patients that had protocol drug discontinuations, because they hit the 45, you should expect us to talk about them four to five of them that happened after increases in doses. So, there'll be more color around those cases. And I just want to reiterate and I think it was basically Anupam, who asked earlier, too, we've got a lot of confidence in how to dose now based on MAVERICK, right? It was a dose-ranging study, where we are -- we drove to higher doses by design in order to get to those edges, where we see reductions in EF that was the point much like we did in the Phase 2 study with PIONEER.
What is really critically important here is that, so by the way, the PK/PD relationships are similar in non-obstructed to the obstructed population. We've run all of those analyses and those are very similar. Really critical here is beyond looking at drug levels is finding the analogue to the obstruction and the gradient reduction that is the clinical measurement that allows us to appropriately dose in a way that is going to increase the chances of us getting to really clinically meaningful benefit with mavacamten and not necessarily overexposing patients of starting low, adjusting based on something that is clinically connected to symptom improvement, peak VO2 improvement, et cetera, much like we have with obstruction, we think we've got that.
So, we'll end up talking more about that after we get through our FDA interaction, which we will not update, who we're not expecting to update, you shouldn't expect us to update that at ACC. We're going to come back later on with the input from FDA and the go-forward plan for non-obstructed, but we can tell you confidence now analyzing the MAVERICK data that we're ready to dose non-obstructed patients with mavacamten.
Gobind Singh -- BMO -- Analyst
Thanks, Tassos. That's really helpful.
Operator
Thank you. Our next question comes from David Nierengarten with Wedbush. You may proceed with your question.
David Nierengarten -- Wedbush -- Analyst
Hi. I just have one. When you discuss the open label study or open label extension to the study, is the decision to go on the extension solely up to the patient, or is it a combined decision of the patient and physician? And can you -- forgive me if I missed it, but can you give any numbers on or percentages of patients that could go on the open label extension? Thanks.
Jay Edelberg -- Senior Vice President, Clinical Development
The vast -- so let me start out with the easy one is the great majority of our patients are actually rolling over into the LTE, both out of EXPLORER and the vast majority of our MAVERICK patients that as well. It's patient's choice to be able to do this. And we know that they're doing patients who have actually may have actually met stopping criteria we discussed, presently are not included, but we look forward to being able to get those folks into the program soon.
David Nierengarten -- Wedbush -- Analyst
Okay. Thank you.
Operator
Thank you. Our next question comes from Jim Birchenough with Wells Fargo. You may proceed with your question.
Jim Birchenough -- Wells Fargo -- Analyst
Hi, guys. I had dropped earlier. So, apologies if this was asked already, but just on the VALOR study, could you maybe talk about what portion of the diagnosed patients with obstructive HCM are being considered or meet some criteria for septal ablation or myectomy. And maybe remind us of what the echo criteria is for making that determination? And what you would -- what level of reversal would you need to say you've replaced the need for surgery? And then I have a follow-up.
Marc Semigran -- Senior Vice President, Medical Sciences
So, for VALOR, we look to what the guidelines are. ACC, AHA as well as ex-US guidelines, all call for, obviously, an obstructive gradient and symptoms that are not relieved by pharmacotherapy. That's what we're basically using for this trial. And we expect that the addition of mavacamten will allow the vast majority of patients to be able to avoid the need for this. And obviously, we're looking for this to be a durable result for these patients. Of note for all, this is not a study where we compare mavacamten versus surgery, but we're looking to replace the need for surgery for most of the patients.
Jim Birchenough -- Wells Fargo -- Analyst
But is there an LVOT gradient level that would qualify someone for surgery, or is it based on symptoms?
Jay Edelberg -- Senior Vice President, Clinical Development
No.
Jim Birchenough -- Wells Fargo -- Analyst
And again, do you know, what proportion of patients are candidates for surgery?
Jay Edelberg -- Senior Vice President, Clinical Development
So, it's the same level of gradient that we have in the EXPLORER trial over 50. And it is -- so that is based on the similar echo gradient there. And it's -- presently, it is symptoms that are not relieved with present pharmacotherapy. So many Class II patients qualified, as well as Class III, Class IV.
Jim Birchenough -- Wells Fargo -- Analyst
And then maybe...
Tassos Gianakakos -- Chief Executive Officer
I was just going to say. I think there is a large proportion of the patients who actually fit the criteria here that Jay just described. That doesn't necessarily translate into number of surgical procedures, right? So just to be clear about that, because the surgery is a challenging one, it's difficult. There are issues associated with it that are minimized to some extent if you're at Mayo or at the Cleveland Clinic, but perioperative mortality further complications. So, it is not one of those things where you see a lot of the folks that qualify for the guidelines that Jay just outlined, just line up and go get the surgery. So, I think there are about 1,000 or so.
Marc Semigran -- Senior Vice President, Medical Sciences
Yes. I mean, when you consider all forms of septal reduction therapy, it's about 1,500.
Jay Edelberg -- Senior Vice President, Clinical Development
1,500 are getting their procedure but I would estimate that it's a pretty significant multiple that are eligible, that don't go on to.
Jim Birchenough -- Wells Fargo -- Analyst
And then maybe just one more question on the hand wringing around ejection fraction. And maybe you could speak to differences between the risk or propensity to reduce ejection fraction in a non-obstructive setting versus obstructive setting, if there's different dynamics at play where you might reasonably expect lower ejection fraction reductions in one versus the other?
Jay Edelberg -- Senior Vice President, Clinical Development
What we're seeing is a similar PD/PK profile in both the non-obstructive and the obstructive patients. So, while one could speculate differences there, what we've seen is much more similarity.
Jim Birchenough -- Wells Fargo -- Analyst
Okay. Thanks for taking the questions.
Tassos Gianakakos -- Chief Executive Officer
Thanks, Jim.
Operator
Thank you. And I'm not showing any further questions at this time. I would now like to turn the call back over to Tassos Gianakakos for any further remarks.
Tassos Gianakakos -- Chief Executive Officer
Thanks very much and thanks, everyone, for all your questions. The team here and I are really looking forward to keeping you updated on a continued progress with mavacamten and across our portfolio. As you heard today, it's going to be an incredibly productive period with a lot of important data to discuss between now and mid-year, including the detailed MAVERICK data at the end of March at ACC, the results of the danicamtiv studies, a little bit later and the topline EXPLORER readout in the second quarter. I hope that we see many of you over the next month or so as we participate in a number of upcoming investor conferences and really appreciate your time today. We're building a really special company here at MyoKardia with an important mission and very much appreciate your continued interest and support. Thank you.
Operator
[Operator Closing Remarks]
Duration: 62 minutes
Call participants:
Michelle Corral -- Senior Director, Corporate Communications and Investor Relations
Tassos Gianakakos -- Chief Executive Officer
Jay Edelberg -- Senior Vice President, Clinical Development
William Fairey -- Executive Vice President, Chief Commercial Officer
Taylor Harris -- Chief Financial Officer
Marc Semigran -- Senior Vice President, Medical Sciences
Anupam Rama -- JPMorgan -- Analyst
Tazeen Ahmad -- Bank of America -- Analyst
Alethia Young -- Cantor Fitzgerald -- Analyst
Ritu Baral -- Cowen -- Analyst
Mark Connolly -- Credit Suisse -- Analyst
Etzer Darout -- Guggenheim -- Analyst
Hannah Lynne -- Morgan Stanley -- Analyst
Keith Tapper -- Citi -- Analyst
Gobind Singh -- BMO -- Analyst
David Nierengarten -- Wedbush -- Analyst
Jim Birchenough -- Wells Fargo -- Analyst
