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MyoKardia, Inc. (NASDAQ:MYOK)
Q3 2019 Earnings Call
Nov 11, 2019, 8:30 a.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 AHA 2019 Data Call.

[Operator Instructions]

I would now like to hand the conference over to your speaker today Michelle Corral. Thank you. Please go ahead ma'am.

Michelle Corral -- Senior Director, Corporate Communications and Investor Relations

Thank you, man. Good morning and thank you for joining us for today's call. I'm yourself around my head of corporate communications and Investor Relations. Today we will be reviewing two sets of data. top line data from our phase two Maverick HCM said is now the champion and non obstructed HCM population and the 48-week results from our PIONEER open-label study of mavacamten in obstructive HCM patients. On the MyoKardia website we have posted the 2 press releases issued this morning. Leading today's call is MyoKardia's CEO Tassos Gianakakos. Tassos is joined today by Jay Edelberg our SVP of Clinical Development; and Marc Semigran our SVP of Medical Sciences. 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 November 11 2019. We undertake no obligation to update or revise any forward-looking statement 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

Hi everyone and thanks for joining us today. It's an important day for our mavacamten program and for where MyoKardia is heading in HCM and beyond with our precision medicine strategy. Mavacamten continues to generate robust clinical responses in patients with HCM as evidenced by a growing body of data. So this morning we'll be going over new data from 2 studies that continue to paint an increasingly exciting picture for mavacamten's role in HCM patient care. First we'll discuss top line results from our Phase II MAVERICK study in patients with nonobstructive HCM. MAVERICK is one of the largest and most comprehensive studies conducted to date in this patient population. The successful study has provided us a treasure trove of data and new insights about this population whose therapeutic treatment options are virtually nonexistent. We'll also review the 48-week data from our PIONEER-OLE study. After one year of chronic treatment with a once daily pill we're seeing sustained and durable improvements among all patients in the study as well as evidence of some remarkable changes to the structure of the heart.

On behalf of the company, I want to thank the patient's investigators and site staff whose dedication and commitment made the studies of success. We're going to be covering a lot of new information on this call, which will try to do efficiently with some brief headlines before we get into the details starting with Maverick. Maverick primary study objective was demonstrating safety and tolerability we've achieved. In addition to demonstrating safety we identified a patient profile with diastolic dysfunction that we believe most likely to achieve benefit from mavacamten. This is a big deal. It's what MyoKardia was formed to do. To give some perspective 3 million people in the U.S. have diseases of diastolic dysfunction referred to as HFpEF who historically have been addressed as a single group and managed in an undifferentiated way with no approved therapies. With data emerging from MAVERICK we believe we can now subtype these patients both those with HCM and those with HFpEF. As a result we'll be advancing Mavacamten's development both in nonobstructive HCM as well as in our first expansion beyond HCM into a well-defined subgroup of patients with HFpEF in a precision-efficient fashion.

Turning to the PIONEER-OLE study. At one year of doses mavacamten safety and tolerability profile remains solid and the treatment benefits are sustained gradient is reduced EF remains above normal with little change from baseline. And patients are feeling better and we're seeing a wide range of biomarkers moving toward normal levels supportive of important improvements in their hearts. Beyond our decisions to advance in nonobstructive HCM and expand into HFpEF the data and insights from both studies have also increased our confidence in EXPLORER in a number of ways. First the safety and tolerability in MAVERICK was very consistent with what we've seen to date. MAVERICK also gave us an opportunity to confirm our expectations for anticipated placebo response and further validate our powering assumptions in EXPLORER. The evidence of long-term benefit and potential for mavacamten to slow or reverse HCM's progression in our obstructive patient population continues to grow. And the diastolic disease benefit observed in MAVERICK adds to our belief that we will see significant clinical benefit in EXPLORER. I know we're excited to get into it.

So let me hand the call over to Jay who will take us through the top line data from our MAVERICK Phase II trial in nonobstructive patients. Jay?

Jay Edelberg -- Senior Vice President, Clinical Development

Thank you Tassos. And good morning to everyone. I'm excited to be here today to talk about the top line results from MAVERICK. Hypertrophic cardiomyopathy or HCM is a chronic progressive disease that changes over time. While some people with HCM might not experience much in the way of symptoms others struggle with ordinary activities and far too many develop atrial fibrillation stroke heart failure and sudden cardiac death. Both the obstructive and nonobstructive forms of the disease genetic mutations that lead to excessive contractions are the same but the ways that the hypertrophy or thickening of the heart muscle manifest can vary. In obstructive patients we typically see significant thickening of the septum near the mitral valve that results in an obstruction to blood flow in the left ventricular outflow track. In nonobstructive HCM the thickening of the heart muscle tends to be more symmetric and the disease manifests are driven by the inability of the left ventricle to expand and fill with blood. MAVERICK enrolled a total of 59 patients representing one of the largest controlled clinical trials in nonobstructive patients ever conducted.

Considering the unmet medical need and prior limited clinical trial data in this population MAVERICK represents a groundbreaking opportunity for mavacamten and our patients. Mavacamten -- sorry MAVERICK is a dose-ranging study. Participants were assigned to 1 of 3 groups each either to receive placebo for once-daily doses of mavacamten targeting 2 EXPLORER concentrations centigram 200 or 500 nanograms per mL. By design some patients were above and others below target concentrations in order to provide a full picture of the right dosing approach. This is notable because prior to MAVERICK there was no biomarker equivalent of the obstructive gradient to guide dose titration. Based on our results we think we have uncovered the markers to identify and dose these patients offering us an important opportunity to make meaningful difference in how nonobstructive HCM patients are treated. The entry criteria for MAVERICK were a diagnosis of nonobstructive disease as defined by echocardiographic guidelines; a baseline ejection fraction of at least 55%; an elevated NT-proBNP and symptoms; New York Heart Classification Class II or III. Baseline characteristics such as gender genetics age fitness level degree of symptoms were evenly distributed between the active and placebo arms. A threshold for diastolic dysfunction was not required for enrollment. One of the first things we noted in this study was a spectrum measures of diastolic dysfunction among the patients.

Indeed only about half the patients had elevated filling pressures and rest is measured by elevated E/e' prime. Now let's turn to the data. First and foremost mavacamten appears to be well tolerated. Adverse events noted in MAVERICK were consistent with prior studies of mavacamten and the majority of AEs were mild or moderateand reversible. Serious adverse event rates were twice as high among the placebo patients compared to the 2 active treatment groups combined. The most serious adverse events in the study were cardiac related. There were 5 patients in the treatment -- with on treatment reductions in ejection fraction below the prespecified protocol levels. These were all transient events and all patients recovered without harm. We are pleased with this safety profile. We have now added 40 patients treated with mavacamten for over 16 weeks to our safety database more than double what we had coming out of our PIONEER Phase II study. Turning to the readout of our exploratory efficacy endpoints. When we look at all patients valuable for treatment effect there was no meaningful separation between the active and placebo arms for peak VO2 New York Heart Association Class or echo measures of diastolic parameters.

There was a dramatic change in several biomarkers of cardiac stress patients receiving men Captain versus placebo. Specifically, we saw a 50% reduction in anti pro BMP levels across both treatment cohorts versus placebo, which was highly statistically significant. As early as week four, we observed a separation from placebo. Even monster patients treated with low concentration, the NP pro PNP reduction or sustained for week 16. This is an important result, given man campaigns mechanisms of action and relieving the excessive contraction in the heart. This is where we wanted to be to see a treatment effect and tells us that our bug is working as hypothesize. As a reminder NT-proBNP is an important marker of cardiac wall stress and elevated NT-proBNP levels are associated with increased rates of heart failure-related death hospitalization and progression to end-stage disease and stroke. Equally important was the observation of clear clinical benefit in 2 patient subgroups a prespecified subgroup with high-scope morbidity and mortality associated with their disease and among those with greater degree of diastolic dysfunction. We have long hypothesized that one reason mavacamten would work well in nonobstructive HCM is due to the positive effects and diastole compliance and filling we have seen in animal models and in the clinic with obstructive HCM.

As could be expected with mavacamten those with elevated left ventricular filling pressures a marker of more pronounced diastolic disease we saw trends differentiating these patients on treatment from those on placebo across the majority of our exploratory endpoints. Peak VO2 NT-proBNP E/e' prime and other diastolic measures all improved in the active treatment group. In a prespecified population of high-risk HCM patients treated with mavacamten resulted in similar trends of clinical benefit among multiple parameters of symptoms function and diastolic improvement versus placebo. What are these data telling us? The wide range of concentrations teaches us where we want to be in a starting dose in the nonobstructive for the diastolic disease populations moving forward. We now have a strategy for dosing based on clinical parameters just like we are doing in EXPLORER. Differentiating activity among the subgroup now informs potential enrollment criteria and endpoints for future clinical trials. We expect an identification of these patient disease markers will also be key in developing effective therapies for HFpEF subpopulations. This is precision medicine in action. Next we're going to continue our analysis of MAVERICK results and are preparing abstracts to be submitted to upcoming medical scientific congress.

We are aiming to present the additional results from these study by the end of the first half of next year. Based on these results our team is excited in developing and optimizing protocols for our next set of studies. We're looking forward to discussions with the FDA in the first half of next year to discuss potential paths to registration in nonobstructive HCM. We're also excited about launching our first Phase II study in patients with HFpEF who we believe can benefit from Mavacamten's mechanism of action.

And with that I'll turn the call over to Marc Semigran who will walk us through the highlights from PIONEER-OLE 48-week data that will be presented at the AHA next week.

Mark Spearman -- Biotech, Life Science and Technology Corporate Communications Leader

As someone who's treated these patients for many years hearing the MAVERICK data is really exciting. As it's a potential game changer for patients with cardiovascular disease. This morning the embargo lifted on the data being presented at the upcoming AHA scientific sessions. There Dr. Steve Heitner Director of the OHSU HCM program will present new findings that have emerged from our PIONEER-OLE study. Not only is this study providing us a continued look at Mavacamten's long-term benefits it is giving us a glimpse into what may be happening in EXPLORER. I'm excited to describe how safety durability and consistency of effect epitomize the results we're seeing in the 48-week OLE data. 12 patients are included in this dataset and remain on the study. The marked reduction in LVOT obstruction reported at 12 24 and 36 weeks is maintained at 48 weeks. The safety profile remains unchanged. Patients are feeling better and across multiple and diverse biomarkers we're seeing signs of their hearts regressing toward a more normal state. In all 12 patients LVOT gradient was consistently and meaningfully reduced whether measured at rest during the Valsalva maneuver or after exercise. A particular note is the postexercise gradient which decreased from 128 millimeters of mercury at baseline to 40 at 48 weeks.

This is new information, as it is the first report of Maverick Hanson's effect on post-exercise gradients in the OLE. It is a dramatic, clinically and statistically significant indication that we are continuing to alleviate obstructions of blood flow with magic hands in therapy. obstructive HCM is a disease that is most apparent with activity. Patients will be able to supply their peripheral organs with adequate nutrients and oxygen when they needed the most while exerting themselves or with other forms of stress. Importantly, LV ejection fraction remained above normal in all patients at all the time. Mavacamten is restoring to normal the frequency of myosin binding to actin and force generation in the heart. This is a direct improvement from the constant cardiac hypercontractility these patients have as the cause of their disease the equivalent of being constantly in fighter flight mode. The beneficial effect of mavacamten normalizing the heart's ability to contract at rest and to increase appropriately when necessary is an excellent example of the results of MyoKardia's precision approach to cardiovascular disease. Mavacamten was well tolerated with no drug-related adverse events observed and no dose adjustments needed. Of note no cardiac AEs have been associated with treatment over the entire OLE study. Patients in the OLE study report improvements in how they're feeling and their ability to function on a day-to-day basis.

When we look across several of the study's symptom and function measurements it is clear that patients on mavacamten are finding durable and meaningful improvements in their symptoms and in the impact of HCM on their daily lives. The majority of patients are now NYHA Class I or asymptomatic. Among the few patients who remain at Class II other parameters including LVOT gradient and NT-proBNP are showing persistent improvements. At week 48 we also asked patients to complete the Kansas City Cardiomyopathy Questionnaire commonly referred to as the KCCQ. Patients' responses to the questions are converted to a scale of 1 to 100 with a higher score being better and an increase of 6 or more being considered clinically significant. KCCQ scores rose from a mean of 74 at baseline to 87 at 48 weeks a 13 points improvement. We've previously presented compelling biomarker data as well. These have included NT-proBNP and E/e' prime which you've heard a lot about from Jay in the MAVERICK study also left atrial volume a measure of filling pressure that is associated with an increased risk of atrial fibrillation. Each of these measures NT-proBNP E/e' prime and left atrial volume have decreased by statistically significant amounts approaching or achieving normal levels. While we view all of these data points as exciting signs of the heart failure -- of the heart functioning better particularly noteworthy is the reduction in the mean NT-proBnP from 1836 picograms per mL at baseline to only 136 at week 48. By way of context a normal NT-proBNP plasma level is 125 or lower.

These changes in parameters of ventricular filling and cardiac wall stress may indicate that treatment with mavacamten is lessening the stiffness of the left ventricle associated with hypertrophy over time. This would improve the left ventricle's ability to relax and fill with oxygenated blood during diastole. We are reporting a new finding with this dataset that joins these other biomarkers as an exciting indicator of a change in cardiac structure for the better. The abnormally thickened interventricular septum which is a defining feature of obstructive HCM progressively decreases from baseline. Specifically when measured by echocardiography at baseline the mean septal thickness in PIONEER-OLE patients was 17 millimeters. After 48 weeks of mavacamten it was 15 millimeters. It is noteworthy that septal thickness was observed in the OLE to progressively decrease at each time point it was measured. This longitudinal change supports our hypothesis that normalizing contractility with mavacamten therapy in oHCM patients will lead to beneficial changes in cardiac structure. By way of context a normal septal wall thickness ranges from 6 to 10 millimeters. According to the AHA/ACC guidelines HCM is diagnosed based on a maximum wall thickness of at least 15 millimeters. Wall thicknesses of 13 to 14 are considered borderline. In addition the risk of sudden cardiac death in HCM patients has been observed in the literature to increase progressively as wall thickness increases above 15 millimeters.

As data emerged from our other studies we will continue to monitor these and other biomarkers to enable us to build a more complete picture of the long-term effects of mavacamten on the heart and its potential for slowing disease progression and reverse remodeling. The prospect of making a meaningful positive impact in the lives of patients is what brought me to industry. I am exhilarated by the improvements associated with the mavacamten treatment that we have observed in our HCM patient symptoms physiology and biomarkers.

The directionally consistent and durable results seen in the OLE study across diverse parameters are nothing short of remarkable. Tassos?

Tassos Gianakakos -- Chief Executive Officer

Thank you Mark and Jay for the data review. So before we open the line up to your questions let me summarize what these data mean for the big picture at MyoKardia and how it sets up our company over the next six to nine months. We're moving mavacamten forward in 2 patient segments in addition to obstructive HCM. As Jay mentioned MAVERICK gives us confidence to advance in nonobstructive HCM and in a subset of of HFpEF. Much like PIONEER guided our design of EXPLORER MAVERICK has generated the data we needed for nonobstructive patients including identifying the analogous biomarkers to LVOT gradient. We're ready to finalize our nonobstructive HCM plans and aim to discuss them with the FDA in the first half of next year. In parallel we'll be taking our first thoughtful step into an adjacent subgroup of HFpEF patients roughly estimated to be about 10% to 20% of all HFpEF bringing our precision medicine approach to one of the largest remaining areas of medical need. Our confidence in the successful EXPLORER trial has also gone up a lot with today's data. Our safety database just grew substantially and mavacamten continues to be consistently well tolerated.

We've looked at the placebo arm in MAVERICK and found that our estimates for placebo response in EXPLORER is spot on. So we're feeling really good about EXPLORER's design and powering assumptions. And our confidence in Mavacamten's efficacy in EXPLORER is supported by both studies today. The OLE of course in the same patient population and the subgroup data from MAVERICK tells us mavacamten is improving left ventricular compliance enabling the heart to fill at lower pressures which should help obstructive HCM patients as well. Finally while early the evidence is mounting that mavacamten may be enabling structural changes in the heart that could ultimately be disease modifying with multiple and diverse markers all improving and moving in concert toward normal. So let's take a look at where MyoKardia will be in 6 to nine months. For mavacamten we'll be through EXPLORER and moving toward our first NDA filing in obstructive HCM. The SRT study will be under way looking at obstructive HCM patients who have been referred for surgery.

The MAVERICK insights you heard about today will have positioned us for registration path and nonobstructive HCM and we'll have started a Phase II study in a targeted HFpEF our first non-HCM indication with mavacamten. For 224 we expect to be reading out data from our Phase I program and we'll be moving into Phase II study in HCM and/or targeted HFpEF. And for MYK-491 we'll be under way in a Phase II genetically defined DCM population and gearing up to drive a precision registration program in patients with diastolic dysfunction. And all the while we'll be mining the proprietary clinical insights from our studies including MAVERICK and EXPLORER which will enable important patient profiling and novel research programs. It's really an exciting time for us here at MyoKardia seeing the vision come into focus which our team is incredibly motivated to make a reality.

So with that operator let's open the lines up for questions.

Questions and Answers:

Operator

[Operator Instructions] Our first question comes from Anupam Rama with JP Morgan, your line is open.

Anupam Rama -- JP Morgan -- Analyst

Hey guys, thanks for taking the question. Just on the EF reduction observed here in MAVERICK I believe in the PIONEER study you saw EF dip below 50% at drug concentrations that were 1000 nanograms per mL. And here in MAVERICK you chose drug concentrations that are lower but it still appears that 5 patients kind of dip below 50%. How are you thinking about EF here heading into the 2Q EXPLORER results? Was there anything particular about these 5 patients' baseline characteristics worth noting when it come to EF.

Jay Edelberg -- Senior Vice President, Clinical Development

So in this study it was a dose-ranging study. So we specifically pushed the dose based solely on concentration without regard to any clinical response. And so therefore by definition we expected some patients to be at upper levels and that their ejection fraction may come down. And that's exactly what we learned. Though what this tells us now coming out of MAVERICK is that we have physiologic we have biomarkers that we can follow to guide our dosing in our future studies just like we're doing in EXPLORER.

Tassos Gianakakos -- Chief Executive Officer

And Anupam just to add what we're seeing here really lines up with all of our modeling our preclinical modeling our earlier studies around PK and effect on EF. And the thing to keep in mind too because your question was specifically around thinking about EXPLORER. Look at that OLE data the EF is really hasn't moved at all for these patients. So dosing in the obstructed patients we feel really good about and MAVERICK is supporting our strategy to dose in EXPLORER. And separately as we think about moving forward in the nonobstructed patient population we feel really good that this data has given us the ability to identify a well-tolerated dose that's going to keep nonobstructed patients in the normal range.

Anupam Rama -- JP Morgan -- Analyst

Great, thanks for taking our question.

Tassos Gianakakos -- Chief Executive Officer

Thanks a lot.

Operator

Our next question comes from Marty Auster with Credit Suisse, your line is open.

Marty Auster -- Credit Suisse -- Analyst

Hey, Ron, thanks for the question. I had a couple. I was wondering if you could provide more detail on the placebo group performance in the ITP versus baseline on some of the functional end points you looked at NYHA and VO2 max? And then also I was wondering if you could maybe provide a little more information on the subgroup with greater diastolic dysfunction where some efficacy measures were observed. What's the size of that subgroup? And how was that defined?

Tassos Gianakakos -- Chief Executive Officer

Marty so let me hit the placebo response rate. Yes this was a key takeaway that increased even further our confidence in EXPLORER. So we had modeled an estimated 25% placebo response. We're looking at the responder definition in EXPLORER and we saw 21%. And so this supports the assumptions in EXPLORER validating the power assumptions that we've got in that study. And we're feeling even better about it after MAVERICK. In terms of the subpopulations this I have to say I'm glad you asked that question it is fundamental to our strategy and to MyoKardia's competitive advantage. This idea of profiling and subtyping patients' clinical trials that we're doing with targeted drugs like mavacamten 491 224 they're generating such important information often proprietary information that we got to be very careful about disclosing for competitive reasons. We've learned a lot about this patient population from MAVERICK. We're going to apply that knowledge going forward to nonobstructed development and to HFpEF studies next year. Some of the things that we're learning from these populations and from the biomarker and imaging profiles are of course how to dose how to select them what measurements are going to matter the most how to dose adjust to a physiological effect which is really important. In MAVERICK we dosed the PK. So it's all really really good. Jay maybe you want to paint a clinical profile of these patients a bit.

Jay Edelberg -- Senior Vice President, Clinical Development

Yes. So we -- so that we actually looked at 2 different subgroups. One we found very interestingly that many of the -- that half the patients that we enrolled actually had at rest lower levels of E/e' prime. So focusing on those who are actually abnormal we're really really pleased to see that those parameters were able to start to normalize over the 16 weeks. So we treat out further. There is opportunity potentially for the others. Similarly as Tassos mentioned we've been able to identify a high-risk population the details of which we'll disclose later on which got a consistent benefit as well with improvements in function and physiology and biomarkers as well.

Marty Auster -- Credit Suisse -- Analyst

Maybe you could clarify Tassos on the comment you made about a 20% response rate in the treatment in the placebo group. What were the treatment group response rates? Was there any dose range? And what is the mean VO2 change from baseline in the placebo group? If you could offer any more detail on any of those questions.

Tassos Gianakakos -- Chief Executive Officer

Yes. So we -- in these groups that have -- appeared to have more congestion whose symptoms are really impacting and limiting their function that Jay just described we saw solid trends in Peak VO2 and New York Heart Association they would qualify for a responder analysis. The magnitude of those changes were similar to what we saw in PIONEER actually. But many other measures in those groups improved as well. So we'll be thinking about that as we consider the design of the next study for sure. In MAVERICK unlike EXPLORER wasn't designed to show optimal effect on the EXPLORER responder definition as we all know. And it's in a different patient population as well with a different dosing scheme.

But nevertheless in these populations which is why we're really excited right is that we're seeing a lot of concordant movements in really important endpoints including peak VO2 and New York Heart. So really what's great to take away is the placebo response rate as you've highlighted here; the fact that NT-proBNP is dropping in everybody and that we're able to really frame out how to think about dosing patient selection and measurements of the right markers for these groups with diastolic disease. So we're talking about being able to help patients with diastolic disease which is really awesome.

Operator

Thanks, doctor.

Thank you. Our next question comes from Ritu Baral with Cowen, Your line is open.

Good morning, guys. I just want to clarify a little bit about those 5 patients that the ejection section drops. Were -- can you confirm that they were at the highest essentially plasma exposures in the range that you were looking at even above the 500 target? And what did you do to resolve them? You said they were transient. Did you dose reduced these patients or did that resolve on its own?

Jay Edelberg -- Senior Vice President, Clinical Development

So let me handle the first right up front. So these were transient and drug was stopped per protocol. In this protocol we did not have a down titration like we do in our EXPLORER program here. So they actually were able to respond very very quickly and they were all transient and everyone is fully resolved here. The next aspect about the specific PK is that we look forward to being able to discuss those when we present all these data at an upcoming scientific congress.

Ritu Baral -- Cowen -- Analyst

Got it. And then can you talk just a little bit about what's the most common SAEs were in the mavacamten just because there was a higher rate versus placebo? Were they associated in those patients with EF drops or were they even cardiac in nature?

Jay Edelberg -- Senior Vice President, Clinical Development

Okay. So let's clarify. The sAE rate the serious adverse event rate was higher in the placebo group than it was in the treatment twice as high overall in placebo's rate compared to the treatment arms. These were highly -- these were largely cardiac in nature and again half the rate in the mavacamten arm.

Marty Auster -- Credit Suisse -- Analyst

Got it. And sorry the SAE or AE just the sort of regular adverse event rate?

Jay Edelberg -- Senior Vice President, Clinical Development

The regular adverse event rates so we'll be reporting those out when we pull out -- when we report out the final data at an upcoming congress there. But overall we are pleased with where it's tolerability in the overall safety profile which remains consistent with what we've seen coming out of the PIONEER and PIONEER-OLE.

Ritu Baral -- Cowen -- Analyst

Okay. And then my last question. Tassos you mentioned that in -- for your HFpEF program going forward you're likely to target a profile that is 10% to 20% of all HFpEF patients right now. Can you talk to what defines those target HFpEF patients? Are they those -- are they the ones with the most diastolic dysfunction? And if so are the current guidelines for diagnosing a diastolic dysfunction -- is that what we can go on? Will that capture that market or will you need measures above and beyond what's in the current guideline?

Tassos Gianakakos -- Chief Executive Officer

So Ritu this -- just to remind everyone listening we've got nothing for -- out there that's approved to help patients with diastolic dysfunction. And my cardiologist colleagues here can attest to that having treated these patients. So we're in new territory which is super-exciting and very important. As we think about how we're going to proceed and you know our whole approach here at MyoKardia which we're starting to see come to light is to take these large heterogeneous patient populations which HFpEF is a classic example of and really start to profile based on underlying drivers and etiology of their disease. So we've had -- we've been working in this area for years. We've been studying profiles both non-clinically and clinically of biomarkers imaging circulating others to help us start thinking about how this framework might evolve and what subgroups might evolve. And so we had some hypotheses going into MAVERICK and we're really happy to learn that mavacamten's mechanism for us we believe is matching what we think will be about 10% to 20% of HFpEF patients who -- as you're kind of alluding to they share a lot of similarities to the more diastolically severe nonobstructed patients that we saw in the subgroups in MAVERICK. So that's pretty exciting. They don't have a genetic or familial HCM. I suspect if we continue to be able to track on this path we're going to be able to influence how these patients are diagnosed but it's new territory here. Marc can talk a little bit about how patients in -- with HFpEF are currently diagnosed and subtype if they are at all.

Marc Semigran -- Senior Vice President, Medical Sciences

I don't -- Tassos thank you. So I think that the ESC guidelines on the diagnosis of diastolic dysfunction are probably the most relevant here. And they do indeed call out these measures of diastolic function that we've been thinking about. They call out E/e' prime left atrial volume e prime itself. So very consistent. Our group in MAVERICK that we're seeing such a striking beneficial response and several of the defining metrics for diastolic dysfunction.

Ritu Baral -- Cowen -- Analyst

Got it. And then sorry last question Tassos. And in answer to Marty's question you mentioned that the magnitude of the responses in MAVERICK were similar to those the in PIONEER. Were those responses at the target dose that you guys plan on taking forward? Or did you see some of those magnitudes in either doses you won't be taking forward or doses lower than the target?

Tassos Gianakakos -- Chief Executive Officer

Yes. So we -- Jay mentioned that we started to see changes in wall stress as measured by NT-proBNP really early in -- within weeks of treatment. So those -- that's happening at low doses Ritu. But what I can tell you is we were looking to find a dose that would keep ejection fraction in the normal range which -- and that would show us improvements along the lines of as many of these clinical measurements that we've been talking about peak VO2 symptoms E/e' prime etc. And we've achieved that. We've achieved that with what we believe to be a broad enough therapeutic index to really take forward and get excited about. The other piece that we were all looking for is we ended up having the gradient that we could not just enrich patients for but also use to dose to an effect with the obstructive population. And we didn't have that going into MAVERICK. So maybe the most important thing or one of the most important things coming out of this work here is that we believe we've got that now. So that really allows us to think about optimizing dose maintaining safety in these patients and balancing ejection fraction with the clinical benefit.

Ritu Baral -- Cowen -- Analyst

No, thanks for taking all the questions.

Operator

Thanks. Our next question comes from Tazeen Ahmad with Bank of America, Your line is open.

Tazeen Ahmad -- Bank of America -- Analyst

Hi, good morning, guys. Thanks for taking my questions. Tassos I just wanted to clarify some time lines. So your team has been pretty clear that this was really a dose-exploring study and we're not surprised to see that certain doses might be too high for patients depending on the situation. But overall does this change -- just based on what you said today about meeting with FDA and talking about time lines does this change in any way your internal pipelines for moving nonobstructive forward? That's the first question. And then my second question is about how you would ultimately think of what a good primary endpoint would be for a pivotal study in nonobstructive? Are you talking about using biomarkers like NT-proBNP or would you feel comfortable using VO2?

Tassos Gianakakos -- Chief Executive Officer

Tazeen yes this does not change our time lines. We saw what we wanted to see in order to ungate our investment and drive forward in nonobstructive which is one -- the mechanism in a nonobstructed patient now it's matching it's working and we're seeing stats-fig on NT-proBNP supporting that. We've understanded how to dose we understand how to adjust dose if we need to adjust dose and we also have a I think wide range of what we're emerging as important clinical measurements to look at for primary endpoints. That's -- we're going to have to have a conversation with the FDA. We've always expected that. And you're right to point out that was part of the plan. We're going to have that -- we're going to look to have that conversation. And part of that conversation will be aligning on the design of the path to register these patients including the primary endpoint. I think some of the measurements that we're looking at are certainly on the table peak VO2 New York Heart. But there might be opportunities to think about some other facets. This is -- this study has given us a lot to think about that could really be helpful. So stay tuned on that. We'll give a regulatory update in the first half of the year. But for us we sell what we needed to see to drive forward and we're really excited about it.

Tazeen Ahmad -- Bank of America -- Analyst

Okay. And if I could squeeze in a last question just on HFpEF. In terms of how well you think that's diagnosed by cardiologists right now can you equate that relative to oHCM?

Tassos Gianakakos -- Chief Executive Officer

Marc do you want to handle that? I mean just to remind listeners the HCM population diagnosis is relatively low. It's about 15%. We believe that with the introduction of therapies like mavacamten we should see an uptick in that. That wouldn't be unusual to see in situations like this. And of course we're working hard to educate the community out there around the disease helping improve diagnosis etc. But we've got some work to do in order to increase that. And ultimately that's what we want to do. And HFpEF Marc?

Marc Semigran -- Senior Vice President, Medical Sciences

Yes. I think that what's generally recognized is that we're going to really need to subsegment the HFpEF population. And that was part of what Tasso and Jay were getting to with identifying those in whom their disease is driven by diastolic dysfunction as opposed to other factors. And that's something that's very much in evolution. And we've been discussing with leaders in the field how we can get cardiologists and even general internists out there to do a better job of that so that as appropriate therapies as we hope mavacamten may well become for HFpEF are deployed that they can be deployed correctly.

Operator

Thank you. Our next question comes from Alethia Young with Cantor Fitzgerald, your line is open.

Alethia Young -- Cantor Fitzgerald -- Analyst

Hey guys, thanks for taking my question. I guess 2 for me. One can you just talk about how you could see benefits relatively rapidly in proBNP and then kind of not maybe take longer to see kind of the effects in VO2 and some of the symptom-based endpoints? And then the second one is just in the dosing strategy did you see there the dose relationship be found? And then just talk a little bit more about targeting dose versus the physiologic symptoms versus concentrations and what you've learned here in nonobstructive then?

Jay Edelberg -- Senior Vice President, Clinical Development

Okay. So let's start out with the drop in NT-proBNP. So we know that NT-proBNP is an important biomarker of wall stress and we saw rapidly that we got a reduction across the patient populations there at a low dose. That's very important. We think that that actually will translate into benefit for many patients. We -- as you would expect that those with elevated E/e' primes would be the ones that would actually be able to normalize whereas those that actually had E/e' primes that were relatively normal at rest wouldn't actually get much better in the short term. Obviously there's an aspect of those who could actually have diastolic dysfunction with exercise that might take a little bit longer to get to. And that we think that this actually translates into our ability to then be able to get benefit by reducing the wall stress. We know that that should translate into the improvements of diastolic dysfunction. And what we've said that we've learned out of this study is then our ability to adjust dose to actually get that benefit for a patient and use that based on physiologic parameters rather than simply just needing to use some sort of PK approach there. And that's very much parallel to how we're approaching it in EXPLORER using physiology rather than concentration which is consistent with how much of cardiology medicine is practiced.

Operator

Our next question comes from Jim Birchenough with Wells Fargo, your line is open.

Jim Birchenough -- Wells Fargo -- Analyst

Hi, guys, congratulations on the results. A few questions. Just a follow-up. Just on the area of therapeutic index are the patients with increased diastolic filling pressures more or less sensitive to reductions in ejection fraction?

Tassos Gianakakos -- Chief Executive Officer

So we're going to hold off a little bit on that information Jim that will be coming in -- I think you're getting at some things that are really important novel insights that are the crux of our strategy and a core competitive advantage. So sit tight on that. What we can tell you is the populations that had these really clear signals across a number of these clinical measurements that showed improvement. They seem to be a group that were a little bit more congested that had -- potentially at higher risk so they could be more progressed and more severe patients which in a study of this size makes sense to see more improvement in this time period in those patients. And we did see -- on the dosing front we're feeling good about the therapeutic index in order to get at relatively low and small changes to EF still seeing a lot of these improvements in this group.

Jim Birchenough -- Wells Fargo -- Analyst

And you may not be able to answer specifically the question but just to the extent that you looked at the responder rate in the placebo group. If you think about the 50% of patients that had elevated filling pressures and abnormal E/e' primes in those patients that achieve reduction in that measure of filling pressure was there a greater response than seen in the placebo? And I'm not asking for numbers but just I want to understand that you are seeing some sort of response that's greater than placebo when you achieve your echo parameter reduction?

Tassos Gianakakos -- Chief Executive Officer

Yes we definitely are. And so when we talk about clear signals what we're saying there are separations from placebo in those subgroups in multiple measurements including peak VO2 and in symptom scoring and in E/e' prime etc.. So -- and the changes that we're seeing are these in this study. And if you were going to go and compare across studies which you have to be thoughtful about the magnitude in those changes are similar to what we saw in the PIONEER population.

Jim Birchenough -- Wells Fargo -- Analyst

And then just finally on the severe adverse events where you saw a twofold increase in the placebo group were arrhythmias captured within that? And could you maybe just comment on rates of AFib and other arrhythmias between placebo and treatment?

Jay Edelberg -- Senior Vice President, Clinical Development

Well obviously arrhythmias were part of what we captured and we look forward to being able to present these data in total at an upcoming congress.

Michelle Corral -- Senior Director, Corporate Communications and Investor Relations

Yes you got it. And just -- I do want to say I mean the background rate of AFib is high in this patient population in general as well as in obstruction. So I think just to remind this is a serious disease and there's a lot going on in the natural history and the background here for these patients.

Operator

Thank you. Our next question comes from Jeff Hung with Morgan Stanley, your line is open.

Jeff Hung -- Morgan Stanley -- Analyst

Oh, thanks for taking the questions. I have a couple on PIONEER-OLE. Between weeks 36 and 48 the left atrial volume index went from 30 to 34. Can you talk about your thoughts on that? It doesn't seem like it's just a small sample since the standard deviation is smaller than the prior time points. So any color you can provide would be helpful.

Marc Semigran -- Senior Vice President, Medical Sciences

Yes. And certainly we'll discuss this further at the presentation later this week or actually next week next -- a week from today at AHA. There indeed is one patient whose left atrial volume is going up and down a little bit but this is still a marked reduction from base one.

Tassos Gianakakos -- Chief Executive Officer

Yes. And Jeff I just want to confirm because I might have heard you wrong. The LA volume index at baseline is 40.9 and between 36 and week 48 it goes to -- from 30.4 to 31.5.

Jim Birchenough -- Wells Fargo -- Analyst

Okay. I might have misread in the book reading image. And then can you help me frame the increase in KCCQ scores in terms of what you think is needed to be meaningful?

Marc Semigran -- Senior Vice President, Medical Sciences

6. An increase in -- of 6 or greater is clinically meaningful. And that's generally accepted. And at 13 we were way above that.

Jeff Hung -- Morgan Stanley -- Analyst

Right. Great. Thank you.

Operator

Thank you. Our next question comes from Mohit Bansal with Citi, your line is open.

Mohit Bansal -- Citi -- Analyst

Wait, thanks for taking my question. A, couple of questions from my side. So you mentioned that now you have a biomarker a biomarker to see the benefit in nonobstructive patients as well which you could use for dosing strategy. Can you please elaborate this a little bit further. What are these biomarkers and how easy are they to measure in the real world clinic settings?

Tassos Gianakakos -- Chief Executive Officer

Mohit yes I'm really glad you asked that because that is really central to what is exciting about this data and really about MyoKardia strategy full stop and precision cardiovascular medicine. So the biomarker profile was one that we we've been researching we've had some ideas on easy-to-measure they were pre-specified as well that's something that we want to make sure is clear in this. In terms of what exactly it is we're going to have to wait on that. I think what we're going to be seeing we hope is more of what we're talking about today with MAVERICK which is gaining proprietary clinical insights from our studies. We've got MAVERICK today. We expect that this is going to happen from EXPLORER. And that really allows us to start bringing the promise of this precision medicine forward here. I mean if we think about this in oncology you see this in companies all the time where they're studying their targeted drugs in a way and really understanding the appropriate patient profile these are core competitive advantages. So when the time is right we'll share that. But, easy-to-measure prospectively defined and really robust.

Mohit Bansal -- Citi -- Analyst

Great, This is helpful. ,And, then maybe another one on the change in wall thickness which seems very interesting. How does this data compare to what we see with ACE inhibitors? ,Asking, because it seems like ACE inhibitors also provide some kind of improvement in wall thickness which could be just because you are just providing symptomatic benefit here and not addressing the underlying disease. So what makes you think that it is probably due to the fact that you are altering the disease here?

Marc Semigran -- Senior Vice President, Medical Sciences

Okay. So just to clarify ACE inhibitors for the treatment of hypertension very different disease actually do provide similar reductions in wall thickness. And it does indeed I think go part and parcel with it. ACE inhibitors are very effective for hypertension. However for obstructive HCM ACE inhibitors are actually relatively contraindicated because they will worsen gradient. On the other hand I think the fact that we're seeing them these reductions in wall thickness with mavacamten really do support that we're getting to that underlying pathophysiology of the disease of the hyper-contractility driving the hypertrophy. So if anything we're the first to show that by attacking that underlying pathophysiology. We're able at least now to say we're seeing signs of alterations of the cardiac structure that is abnormal.

Mohit Bansal -- Citi -- Analyst

Congrats on the progress.

Tassos Gianakakos -- Chief Executive Officer

Thanks Mohit.

Mohit Bansal -- Citi -- Analyst

Great, thank you very much and come back from the province.

Tassos Gianakakos -- Chief Executive Officer

Thanks for him.

Operator

Our next question comes from George Farmer of BMO Capital Markets, your line is open.

George Farmer -- BMO Capital Markets -- Analyst

Thanks for taking my questions. I'd like to drill down a little bit more on these SAEs that you talked about. Can you say whether there -- if there were any deaths or episodes of cardiac arrest in the trial?

Jay Edelberg -- Senior Vice President, Clinical Development

There were no deaths or arrests in the trial.

George Farmer -- BMO Capital Markets -- Analyst

Okay great. That's good to hear. And regarding a registration plan for nonobstructive I mean you talk about these subgroups versus kind of like the complete broader population. Do you think a registration plan would move forward in one of the subgroups rather than the broader population? And what do you think would be a suitable endpoint? Do you still think NYHA and exercise capacity are the right way to go?

Tassos Gianakakos -- Chief Executive Officer

George those are definitely on the table based on MAVERICK. MAVERICK certainly provides evidence to support those in this patient population. But we've got a ton of additional data to really look at assess and discuss with the FDA. So we'll come back with the specifics on the endpoint in the first half. But in terms of the subpopulations everybody in the study despite their E/e' prime level showed improvements in wall stress that were statistically significant and clinically meaningful. So the let's say the population with less elevated filling pressures is one we're going to understand and study a little bit more. Most of these patients the vast majority of patients in MAVERICK have rolled over into the MAVA long-term extension.

We're going to be understanding it wasn't simply that they needed a little bit longer on treatment to see stronger signals? Is it simply just we had a smaller N? Or are they earlier in their progression of disease? All questions that are on the table so it's a group that we're going to continue to understand we're committed to studying. So it's too soon to say whether we'll be driving forward in the subgroups that were prospectively defined and that we're seeing with more congestion here. And we're going to learn a lot while we're designing these studies talking to the FDA from the long-term extension study that's under way.

George Farmer -- BMO Capital Markets -- Analyst

Okay. And one more if I may. Regarding the patients that experienced the lower ejection fraction did that occur earlier on in the study and were they dispersed between the 2 treatment arms? And then were they allowed to continue in the long-term extension?

Tassos Gianakakos -- Chief Executive Officer

Yes. So the vast majority were in the higher concentration dosing arm of those patients and the relationship there is consistent with what we've seen in the past with mavacamten. In terms of whether they were allowed to move on to the long-term extension I don't -- I'm not sure about that George. We can get back to you on it.

Jay Edelberg -- Senior Vice President, Clinical Development

We'll be -- now that we've actually got all of our learnings out of our dose response and how to dose these patients we can then be able to adjust our protocols so that we can allow everybody to be able to put in -- be able to benefit from continued dosing.

Tassos Gianakakos -- Chief Executive Officer

One thing we did not -- we were not able to do for the protocol is provide a dosing holiday or reduce the dose once they hit the stopping criteria. That was just hardwired into the protocol. And of course EXPLORER is very different in that regard.

George Farmer -- BMO Capital Markets -- Analyst

Understood. Great. Thanks very much.

Tassos Gianakakos -- Chief Executive Officer

You got it.

Operator

[Operator Instructions] Our next question is from Etzer Darout with Guggenheim Securities, your line is open.

Etzer Darout -- Guggenheim Securities -- Analyst

Hi, thanks for taking the question. Just a couple here. So first one is to clarify from your earlier comments on the HFpEF population. As far as the 10% to 20% of HFpEF patients that could sort of gains benefit from mavacamten is this subset of patients incremental to the nonobstructive HCM patient population? And along those lines I'm not sure if you mentioned this earlier but I wondered if you could talk about the percentage of patients maybe in the drug cohorts that fall into of the subgroup of patients that saw a benefit? And how easily identifiable these patients are for future trials?

Tassos Gianakakos -- Chief Executive Officer

So to your first question yes the HFPEF subgroup that we're taking forward is incremental to the HCM population including the nonobstructive HCM. So we're aiming at now 3 groups of patients here 2 within HCM obstructive nonobstructive and this targeted subsegment of HFpEF. Your other question...

Marc Semigran -- Senior Vice President, Medical Sciences

It was about the percentage fall into subgroups.

Tassos Gianakakos -- Chief Executive Officer

Oh that's right and whether they're easily identifiable. And the answer is they're definitely easily identifiable. This is one of the great things that we're learning here is we're moving away from more qualitative kind of descriptions of conditions and getting to hard measurements that are echocardiographic circulating biomarkers etc. And that's exactly where we want to be. We did comment earlier that the E/e' prime population was about half had elevated filling pressures the prespecified high-risk population we're not disclosing at this time.

Etzer Darout -- Guggenheim Securities -- Analyst

Got it. And just another question. Sorry to go back on the 5 patients with ejection fractures that fell below the 45% threshold. But I guess ultimately have you learned enough about the ejection fraction changes in these patients as far as biomarker screening etc. that would help predict these changes moving forward in patients you enroll in the future trials? Just sort of your level of comfort in that you sort of understand the dynamics that resulted in these changes and how you sort of want to look at these parameters sort of moving forward in trials?

Jay Edelberg -- Senior Vice President, Clinical Development

Yes. So remember that in this study patients were dosed solely based on concentration without regard to any clinical response. Now that we've got these data in hand and we've got biomarkers both of risk and the efficacy that we can follow we are feeling good about our ability to develop protocols to be able to treat these patients and avoid any reduction in the ejection fraction much the way that we've been able to do in EXPLORER talking on clinical parameters not PK.

Tassos Gianakakos -- Chief Executive Officer

Exactly. I mean I think very analogous in terms of dosing with respect to EF with what we've seen in PIONEER going from PIONEER to EXPLORER. We had transient excursions under normal in PIONEER dose-ranging study was expected. Same type of thing here in MAVERICK. We take those learnings into EXPLORER into the next studies in MAVERICK. And now what we're seeing in the open-label extension right is really validating that for the obstructive patient population. We really understand how to dose to pharmacological benefit with preservation of the ejection fraction. It's really nice to see over 48 weeks.

Etzer Darout -- Guggenheim Securities -- Analyst

Congrats on the progress.

Tassos Gianakakos -- Chief Executive Officer

Thanks Etzer.

Operator

Thanks. So, our next question comes from David Nierengarten with Wedbush Securities, your line is open.

David Nierengarten -- Wedbush Securities -- Analyst

Hey, thanks for squeezing here Just a couple of questions. First off on patient characteristics at baseline or the patients where you saw more improvements and also declining more rapidly prior to entry into the study. And either peak VO2 or NYHA or other measurements. And then are you confident in the next steps for nonobstructive HCM that you have the right dose to see a benefit in peak VO2? Or are you thinking that you're likely to see or use other endpoints for the next study in nonobstructive?

Tassos Gianakakos -- Chief Executive Officer

Yes. So we have confidence in our ability to dose now to see improvements in these patients with nonobstructed HCM in measurements including Peak VO2 whether that ends up being a key component or the -- or other primary endpoint stand by on that David. In terms of more about their profile coming into this study and whether the subgroups who had a different history etc. standby on that one. As we get closer and we get near the data publication and later we'll have more to say about all of that.

David Nierengarten -- Wedbush Securities -- Analyst

I guess just a quick follow-up. I mean the basic question is do the patients who saw a benefit of course resemble non -- obstructive sorry obstructive HCM patients minus the actual obstruction in terms of peak VO2 NYHA improvements here or other improvements. And can you speak to any of that?

Tassos Gianakakos -- Chief Executive Officer

Yes. I see what you mean. And the answer is yes. With the absence of the obstruction of course the baseline characteristics on things like peak VO2 New York Heart Association all of those are very similar. and it's also interesting to note too that they have in the obstructed population the degree of elevated filling pressures is high.

David Nierengarten -- Wedbush Securities -- Analyst

Yep, Thank you.

Operator

Thank you. This concludes the question-and-answer session. I will now turn the call back over to Tassos Gianakakos for closing remarks.

Tassos Gianakakos -- Chief Executive Officer

Well thanks very much. Well I appreciate everybody's time on this call. There was a lot to digest here. It's really -- for us we sit back and we think about when we started the mavacamten program about six years ago there wasn't a whole lot of precedent for applying a precision medicine approach to cardiovascular disease treatments. And with every study we are exponentially adding to our body of knowledge about our drug our endpoints these diseases and importantly about the inner workings of the heart muscle. The data we've shared today are clearly important for our mavacamten program but we view them as significantly contributing to the big vision of changing the lives of people with serious cardiovascular disease. It is a big vision and it's going to take time and dedication to achieve. But with every new dataset and datasets and insights like we got today with MAVERICK we're learning more and more and that's going to help us get us there. So thanks for your continued support on this journey. We look forward to seeing some of you this week at Credit Suisse and at the American Heart Association in Philadelphia next week -- this weekend.

Operator

[Operator Closing Remarks]

Duration: 66 minutes

Call participants:

Michelle Corral -- Senior Director, Corporate Communications and Investor Relations

Tassos Gianakakos -- Chief Executive Officer

Jay Edelberg -- Senior Vice President, Clinical Development

Mark Spearman -- Biotech, Life Science and Technology Corporate Communications Leader

Marc Semigran -- Senior Vice President, Medical Sciences

Anupam Rama -- JP Morgan -- Analyst

Marty Auster -- Credit Suisse -- Analyst

Ritu Baral -- Cowen -- Analyst

Tazeen Ahmad -- Bank of America -- Analyst

Alethia Young -- Cantor Fitzgerald -- Analyst

Jim Birchenough -- Wells Fargo -- Analyst

Jeff Hung -- Morgan Stanley -- Analyst

Mohit Bansal -- Citi -- Analyst

George Farmer -- BMO Capital Markets -- Analyst

Etzer Darout -- Guggenheim Securities -- Analyst

David Nierengarten -- Wedbush Securities -- Analyst

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