Q4 2019 Earnings Call
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I can answer session asking question during the session you'll need to press star one on or telephone. Please be advised the today's conference is being recorded you require any further systems. Please press star zero.
I'd now like to Kinda conference over to your Speaker today, Michelle Corral. Please go ahead Mike.
Thank you Josh.
Good afternoon, and thank you for joining us on today's call I'm, Michelle Corral My parties. It myocardial executive director of corporate Communications and Investor Relations today, we will be reviewing fourth quarter and you're in financial results for 2019, I suppose discussing recent progress in upcoming milestones across our portfolio a press release detailing the financial return.
So with issued earlier this afternoon and is available on our website.
Leading today's call is my cardiac see El Paso's young that's possibly joined today by Dr., Jay and over our SVP of clinical development military our Chief commercial Officer, and Taylor Harris, Our Chief Financial Officer, following their prepared remarks, well open the line for Q anyway.
As a reminder of the information discussed during this call will include forward looking statements, which represent the company's you 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 todays press release as well as our filings with the FCC front.
Information concerning risk factors that could cause actual results to differ materially from those expressed or implied by these statements like.
Ill now hand, the call over trustee yeah. Okay. Thanks, Michelle good afternoon, and thanks for joining US today are companies just a few months away from pivotal data, which we expect will enable us to file myocardial first new drug application with the FDA.
Coming off the year that really highlighted the breadth of our science and our pipeline, which now includes candidates to potentially help people with obstructed HCM nondestructive HCM specific forms of pets have genetic DCM and other forms of just always heart failure.
Assuming continued success, we see myokardia ushering in the Aero precision medicine broadly in cardiovascular disease management, enabling functional cures for many of the millions of people worldwide suffering from heart failure changing their lives in ways, we witnessed in other precision disease areas.
Well, 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 to preclinical programs and multiple additional research. These programs all home grown and discovered by our Myokardia scientist.
This year, you'll continue to see this approach an action with both Mab account in Indiana captive.
The next in a series of near term proof points from ever Cantor would be the release of the complete Maverick trial data the largest and most comprehensive study conducted to date in unobstructed HCM at the American College of Cardiology in Chicago in March.
Results have been accepted for late breaker presentation, those data enabled us to move advocate Hampton forward and non obstructive HCM, which was the main purpose of this groundbreaking study.
In addition, the Maverick trial validated our hypothesis about Maverick hamptons potential to benefit people, what certain types of diastolic heart failure.
And not to be overlooked Maverick further increased our confidence in the phase three explore trial in obstructed HCM.
The second quarter, we'll be sharing the topline results from explore which we feel great about between now and then we'll be discussing the opportunity that we see in diastolic heart failure, often referred to as have pets.
And why we believe our approach to tackling the syndrome affecting millions of people can make a meaningful difference where no therapies have yet to be developed.
Around mid year, we plan to present data from our phase two study of Dan a captive formerly known as MRK for nine one.
The data from our Dan a captive program. So far there really encouraging supporting our decision to initiate a phase two study in people with genetic genetically defined dilated cardiomyopathy.
These genetic abnormalities contribute contributing to the disease are estimated to present in about 30% to 40% of all DCM patients.
As with all our programs, including the Captain. This study has been designed to both provide us with a robust signal of danna Kimptons mechanism laying the foundation for an efficient development path in this targeted patient population.
As well as gain insights on the impact that improving stalick function without detracting from diastole can have in a broader subset of DCM patients.
Today, we'll be focusing on the have accounted for HCM.
Jay is here with me to review some of the key aspects of the explore study and upcoming read out.
We're also joined by built very our Chief commercial officer will share with you some of what we're learning about the burden of HCM and the gaps in the current treatment landscape will also discuss our market development efforts. Finally, Taylor will round out the call with a summary of our financial position and I will recap many of the important anticipated 2020 milestones to come.
Jay.
Thank you talked a good afternoon everyone.
Now ill touch on several key aspects of the phase three explore study.
Namely dosing in safety powering assumptions and the composite functional endpoints.
Explore is the largest and most comprehensive randomized clinical trial obstruct hypertrophy corporate cardium, while he conducted to date.
With more than 70 sites across 13 countries enrolling two 151 patients with symptomatic obstructive Hcl.
Let's start with the individuals dose.
From pioneer in an orderly, we learned how to dose Nova Kimpton instructor HCM based on clinical response.
Namely reduction of locked in for <unk> outflow track radio.
When we don't know accounting to reduce ultimately gradient, we've observed whom it multiple parameters, including antimicrobial he going crushers and left do you feel volume.
Oh welcome trickle rejection products remained in a normal range.
And it's more patient starts on the logo five milligrams novocure and can be increased due to time points to further reduce the obstruction no oh beauty if needed.
Starting will gradually increasing is how we expect novocure would be used in clinical practice.
Turning to the endpoints watchman pound.
Our composite functional endpoints is designed to capture improvements and symptoms in cardiac function using in wage reclassification and mergers of peak real too.
The composite functional endpoints is a foreign why achieving either increasing PPL. Two one we bought no liters per kilogram per minute, we're more damn improvement runway class greater than one one or more.
Or increased to three or more and no worsening human wagering class.
Well listen exporters willpower greater than 95% to detect a 24 point delta between active and placebo.
Our powering assumptions are based on 20 on a 50% treatment response rate.
We derived or assumptions for the placebo response rate of 25% after looking at other studies that incorporate motions with symptoms and function, notably the going on Liberty study.
In addition to placebo responses observed in Melbourne, when applying the composite functional endpoints was 21%.
Having to our confidence in our estimates for the interest would see response and explore.
It's minimal was designed with an assumption for up to 15% discontinuation.
Without sharing specifics I can say that were well below that way.
Patients explore our stadiums starting with the great majority joining the long term extension study.
In addition, explore enrollment so apparel store target of 220, adding further power to the trial.
Well, it's for the Idmc has moved on quarterly basis, we have received agreement with each review.
And explore we will look several key.
Usually beyond the composite functional endpoints.
We expect to see a reduction in grade.
Our base case is to achieve statistically statistical significance versus placebo.
To feel really good about the clinical impact.
We hope to see meaningful reduction ingrained in the majority of patients.
From pioneer and studies, where we know that reductions and ill be OTI obstruction lead to improvements in symptoms.
We want to see an why actually classification improve in this double blind placebo controlled setting.
Ill now open label single arm studies pioneer pioneer hourly labor accounting treatment resulted market changes and one actually class with 70% to patients improving by one glass.
In the placebo controlled explore trial, we believe that an improvement in and wage reclass majority of patients on treatment would be meaningful.
Finally, we will look at PV or to a measure of cardiac function.
Cardio pulmonary exercise testing is mostly going to standard by which we can measure improvements in the heart function and we'll look for improvements and pick bureau to treatment versus placebo.
As we drill results explore we believe these three parameters along with drug safety will be the most critical we are highly encouraged that we have observed improvements in all these various inner studies is now the captain today as well and snowball the Biomarkers improved heart health.
All explore patients are now through the dose adjustment period. So we're in the home stretch remain on track to report topline data in Q2.
Our topline read out will be based on the data gathered through week 30.
At the top line data read out we anticipate reporting on the primary composite functional endpoints and secondary endpoints. The NYSE reclassification PBR to an elder your t. gradient as well as safety and Tolerability.
Export is the key study in our comprehensive registration program.
From all our studies.
Now the cap will be part of the submission, including our long term extension study those novelty that will increase for safety database.
Supplement to our anticipated filing will be the valor HCM trial, which are study started in Q2 in patients will be evaluated principal reduction tariff.
We partnered with the Cleveland clinic, and many other top notch surgical centers see above accounting treatment may provide an alternative to invasive procedures for these patients.
I'd like now.
Turning over to Bill Burns, our Chief commercial Officer, Bill. Thanks, Jay just to pick up for a moment US nothing there was just saying what are the things that makes my job that easy or is that are now the kimpton program 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 export trial design dresses a number of though.
For example at the top of their list just behind a mortality benefit is improvement of any way to say class improvement of symptoms and increasing exercise capacity as measured by Pico too and reduction in left ventricular outflow track gradient are also highly valued product attributes.
So sitting where we are now we feel quite good about dataset explore should deliver.
I might also that our valor study, which will evaluate now the captain as an alternative to settle reduction therapy should provide additional evidence that matter camp in Canada, Ross another serious aspects of the disease.
Being the avoidance or reduce need for us our tea and this is clearly valued by cardiologists.
As we look ahead towards what we anticipate will be a positive read out for spore there's a tremendous amount of work that's been ongoing to understand and develop the market.
Well, we've determined that this is the disease category that has been underserved for a long time due to the limitations of current therapies and that there was an express need for targeted therapeutic options.
The commercial and medical affairs teams are planning for success and we currently laying the groundwork for an eventual market introduction amount accounting for obstruct debates yeah. We're building a very capable team the significant experience in rare and specialty disease areas and so far we brought onboard heads of marketing market access commercial operations ads.
To see field medical real World evidence and health economics.
Now what aspect of our work has been to better understand the burden of disease on patients and their families and the more we talk is representatives of the same community the better we understand the profound impact is in house on patient slots.
So what is what is life like for patients with these yeah.
Well, we know it's a chronic progressive and typically inherited condition and while there are various estimates rate seems prevalence. The most reliable epidemiology study site. One of every 500 people worldwide are affected by HCM. Today. We think there are about 100000 patients diagnosed and treated here in the U.S.
Which is roughly 15% to 20% overall problems and two thirds of these hundred thousand habit via truck performance disease, while the remaining once they're not obstructed.
Fatigue shortness of breath palpitations exercise intolerance and are chest pain are all symptoms of the condition.
Also the symptoms can be settle it can be confused with other illnesses such as asthma.
As a consequence HCM is under diagnose back you can take multiple years for patients to be correctly identified is having the condition.
The way CN presents maybe quite different from person to person.
Even among patients with known underlying mutations the course of their disease can be highly very we've met families with dozens of members who share the same pathogenic mutation.
Where one sibling they trajectory diet sudden cardiac arrest of the young age and another will need a heart transplant into their forties and yet still another simply want developed decent until very late in life all from the same family.
The disease burden can be significant HCM patients over three times higher mortality rate when compared to that of the general use population a similar ages and while relatively rare sudden cardiac death is it very real risk associated with the condition.
The patients have told us that there are many days, where they can't walk down the C block without resting.
One patient said that they want even try to walk out of each any longer.
Some days, it's a it's like an elephant sitting on their just.
The avoid the subway because of the stairs and.
And one patient limited that their shortness of breath and so severe now they can no longer soon.
And the list goes on.
There are forced to scale back basic activities of daily living to accommodate their disease, sometimes so gradually but they're not even cautious of the measures that are taking.
This is common practice.
So these patients are sick some very sick.
And we know the current therapies will help some are not adequate for many.
Now I'd like to shift gears.
Sure some of what we now about who's treating these patients.
We believe that the vast majority of the diagnose patient population are under the care cardiologists.
Our analysis of claims data suggests roughly 75% of these patients are managed by community cardiologists and approximately 25% or managed by doesn't did it seems center for heart failure centers here in the U.S. and we think there's probably around 60 of those in total.
When we look at this another way, we believe that 80% of diagnosed patients are seen by 10000 cardiologists and 50% of these stations are seen by approximately 2800 cardiologists. So this is a relatively concentrated manageable position 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 sciences and field based medical liaisons are establishing meaningful relationships with the cardiology community.
During this should drive conversations around the mechanism of disease, the underlying profit Genesis 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 an adult elevate these conversations and broaden our reach across a community to include a wider population vps patients and payers.
Additionally, we've enhanced our deep disease education efforts, we debuted the exposed HCM disease awareness campaign at AJ last November and we're releasing an accompanying online resource for physicians the spring.
It's also worth mentioning that are real world evidence team.
Kicked off a series of studies examining the burden of illness, HCM natural history and associated risk factors as well as evaluation of associated clinical and economic values.
We're partnering with the largest professional organizations to create custom impactful initiatives to further engage the community in a dialogue about the very real burden life, but HCM.
Recently, we kicked off a formal three year campaign in partnership with Ha designed to heighten awareness and clarify some misconceptions that east in the one cardiologists patients and their families. These new initiatives complement our other long standing contributions to the it's in community such as the share registry the development the skin care attitude and our part.
Ownership, the 23 and meet our commitment is to continue to drive education awareness and engagement around it stand up to and throughout potential launch and look forward to periodically providing updates on what we're learning and Howard developing the it's in market and our approach to the commercialization amount accounting and the lead up to our anticipated launch.
I'd now like to hand over to Taylor's going to walk us through.
The quarter's results Taylor.
Thanks, Bill 2019 was a year a 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, our total operating expenses in 2019, excluding the 80 million dollar repurchase of royalty rights from sanity were $208 billion, that's compared to 107 million in 2018.
Of that R&D expenses for 2019 totaled 146 million and Dziennik DNA expense was $62 million.
The uptick in 2019 expenses reflected increased R&D spending relates the advancement of matter Canton, Dan a captive in Y K two to four and our preclinical programs as well as an increase in personnel and related costs.
As of December 30, Onest 2019, we had $430 million in cash and investments.
So we enter 2020 fully funded to execute on all of our plan to operational activities to the middle part of 2021 more than a year past the expected topline data readout for explore.
Included in this runway projection is the full registration program for Magic Hampton Inn Obstructive HCM.
And the ability to aggressively advance our magic Hampton franchise in diseases of diastolic dysfunction.
As well as our plans to bring Dan a captive and why K to Q4 to the next stages of development assuming encouraging data.
Into advanced at least one of our emerging preclinical programs too and I and the 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 HCC.
The top line explore retail dramatic Hampton Inn obstructive HCM.
A regulatory update and go forward plans dramatic Hampton Inn, not obstructive HCM.
The initiation of our Valor HCM study looking at NAVC Hampton as an alternative to septal reduction therapy.
Initiation of a proof of concept study of Magic Hampton Inn, a targeted desktop population and then for Dana camped is the presentation a full phase two a data and the initiation of a phase two study in genetic DCM.
Our momentum should continue moving into the second half of the year with data at both yes, the and Asia, including the full presentation of our phase three explore results.
Hotline data from our phase one study in Y K two to four.
The initiation of the in Waikiki Q4 phase two study.
And in the background, we will be hard at work on our anticipated in the a filing advancing our disease awareness campaign building, our us commercial infrastructure.
Exploring rest of 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 of this inline with our precision medicine approach with.
I would now like to open the call up to your questions. As a reminder, here with me into also are Dr., Jay Albert and Bill theory.
Thank you as a reminder to ask a question you'll need to press star one on your telephone.
Good question press the pound Keith please standby.
You in a roster.
First question comes from.
I knew from Rama with JP Morgan you May proceed with your question.
Hi, guys. Thanks, so much for taking the question.
And on Madrick HCM APC.
Later next month wondering what level of detail, we're going to be getting on sort of drug concentrations of matter camtek.
On the efficacy side, and then potentially safety insight that we might be able to get from that type of data. Thanks. So much.
So we're going to be presenting the comprehensive clinical data the safety the app because see we'll be looking primarily.
Biomarkers and also giving the details and subgroup analyses.
That we found the greatest response in there and to provide the correlations that give us our path forward in both the and HCM population as well as the reason to believe in the diastolic. This function the health sub populations, we think we can treat.
Alright, Thanks for taking my question.
Thanks helpful.
Thank you. Our next question comes from to Zeena mind with Bank of America. You May proceed with your question.
Hi, good afternoon guys.
Thanks for taking my question, maybe just terrific for two part of your prepared statement you said that all patients.
Having now completed the dose adjustment period, so that the lock then can you provide a little bit more clarity on how long it does take to clean up the data and to report topline.
Hey, it's housing this is taylor so.
We are we're right on track, we're right, where we expected to be the we're expecting just for for the data cleaning process into 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 up.
Endpoint anymore than that just because of the nature of that process.
Okay fair enough.
Can you just clarify what preclinical tox work has been down our needs to be done.
Yes.
Pending positive results.
All the preclinical work is.
Been completed or.
It is being will be part of the submission. So there's nothing that is rate limiting.
Okay. Thank you.
Thank you. Our next question comes from at least two young with Cantor Fitzgerald. You May proceed with your question.
Hey, guys. Thanks for taking my question I.
I just want to talk a little bit about how to think about ejection fraction.
Got it hadn't then thats right, obviously, there's magic ways either for safety, but are there any other points of interpretation and then that's maybe a commercial on how do you guys think about kind of getting the population bigger than the claims population hundred thousand that 500000, whereas the strategies that you're deploying there. Thanks.
Yes, so we went into the injection fraction. So the explorer program is based on clinical based parameters, whereas our phase two data was using basically only dose ranging so with this we're able to dose of just add on.
Are able to avoid any.
Significant drops in E.
Our patients can actually have a dosing holiday in the case, there, yes drop below 50% and then able to get back on the drug to finish the trial. So far all of our numbers indicate that this was working out well.
I'll leave here just to take on a little bit I think a way to think about yes.
Going forward is really to look at.
Periods of prolong the depression on natural depression of the ETF that might lead to heart failure.
This is something that we feel really confident we can avoid both in the construct of 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. So yes, you've got really consistent and stable efficacy and we've got now that confidence.
Since 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 explore so for explore specifically the things to keep your eye on as it relates the F is really kind of Tolerability of may have a camp and that might lead to heart failure. We've got around that the clinical community has got their eye on that and that.
I think is the important consequence from a safety standpoint, FDF from an efficacy standpoint, I mean really what we're looking at is getting rid of the obstruction in a way that essentially maintains F. In a normal range, increasing stroke volume improving symptoms lowering filling pressures et cetera, and you will capture that and the composite endpoint.
In New York Heart and in Peafiel too for the Maverick and unobstructed population, what Maverick really did for US is it gave us the ability that to tune in the dosing in very much. The same way. So now we've got a lot of confidence coming out of Maverick that we can dose than unobstructed patients safely up to their target.
Knowing where that target is for any individual patient in a way that will drive 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 get improve symptoms and improve function in patients.
I mean, let bill if you remember as build the.
Second part of the question.
It's a great question so.
I think the first point is not overlook that they're roughly 70000 patients that are diagnosed and treated with these today. Many of them. We believe are suboptimal. So I think I think for the first couple of years of launch we've got we've got our hands full tremendous opportunity now starting now and throughout throughout the launch phase there is going to be.
A big effort in growing the market, which is what you're getting it right. How do we increased diagnosis of this population and get them in into the proper channels.
There are some so things we're doing the honors and things were planning to do so we launched ZZ campaign, which is really focused now on increasing awareness, we're going live with the website linked to the campaign.
At the end of March, which which will help again I think improve.
The physician awareness around disease and help improve diagnosis.
Once we get we've got this partnership with AJ. So weren't as we're in a position now I think to two promulgate information with the agency out too.
Their entire.
Followership around around each Jim This is a HCM focused initiative with them and then there are some of the kind of the kind of the more fundamental things that we'll be doing some get closer to launch I mean, we're going to invest heavily in c. I mean, we're going to invest heavily in medical education, and speaker programs and bring that bring the.
The care wells in the an expert out to the community to help increase awareness and diagnosis and we're going to be working with the community to refer you get these patients for whom they suspect they submit be it caused it to get them into a center quickly. So there's not there's a whole bunch of things that that we're going to be doing to increase.
Diagnosis.
Okay and answers your question.
Thank you.
Thank you our next question comes from.
Alan You May proceed with your question.
Good afternoon, guys. Thanks for taking the question.
I.
I'm going to focus my first question on your let's see well controlled.
Sorry, your expectations, but well keep up with floor, you mentioned that using the composite criteria you both group and Maverick had a 21, 21% than had a response.
Let me also base.
You basis office.
Usually at Liberty study can you talk a little bit.
The.
The demographics.
People group and how that would how that's comparing in shaping up to the demographics of the placebo group in a floor.
Is there reason that you think that the placebo response will be higher in non of I'm, sorry in obstruct petitions versus the Maverick nondestructive patients like how should we think about that and it's got a falling for bell.
So we estimated us originally off of the Gilliat study, which was a combination of constructive non instructor and that we estimated at 25% we used our own data.
With Maverick and we found that it was a 25, 21% so that means feel very good question, specifically about the demographics.
The patients in Maverick looked demographically very very similar to those we enrolled person pioneer and then in explore except of course the patients in the Maverick trial did not have a obstruction.
There was the only difference knows so based on all that they told US that are placebo assumptions were basically Dallas based on our ability to conduct a placebo controlled clinical trial. So we're pleased about this.
And then a commercial question on the different endpoints that go into the composite I think you listed the.
You rank ordered sort of the secondary endpoints and it sounded like it was in order of importance. The listed in your current Association.
Then.
You know too and then gradient.
The commercials perspective is there.
Meaningfulness threshold that you need to move the needle on and weight change in order to make the best to in order to put your best commercial foot forward.
Well I think showing class improvement is what the community is going to be looking for I mean can we move the needle in a way Jay and I think you know moving one classification is fantastic so not easily accomplish.
And these patients as you heard earlier had a pretty significant burden of disease and a lot of it is limited in terms of the way they they they conduct themselves do activities and quality of life and it all comes down a lot of it comes down to symptoms.
And ability to exercise so.
I think if we're able to demonstrate improvement Buxton class.
We're.
We are providing the community was something they've been looking for for a long time and the quantitative research that we've done that supports that.
You need to show like a certain percentage of patients need to actually hit the anyway James Friedman.
Versus you know.
Peafiel too I guess im wondering like if the composite.
If the composite is more one side versus the other side.
Just one profile present a.
Much more.
Sorry commercially compelling proposition in the real world.
I think I.
I think both sides. If we can think about it both sides are pretty compelling.
In the combined endpoint addresses.
The.
The NYSE component and also that the PPL, two which is very objective measurement of cardiac function.
So I think both are values.
I think that you know and really I mean, we don't have much more to too just to say on that if I look at the attributes list Pico twos, just behind and way Jay.
I guess it would depend on who you ask.
Okay no actually.
Sorry.
So you can think about Peafiel two is your maximum output that that's your real scripting capability. We know patients are limited by that NYSE Chase more of an integrated how are you doing activities of daily living. These are both very important to me as the cardiologists. 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.
Got it thanks, Mark and one quick last question, what do you guys thinking right now in terms of the commercial forced to maybe hit those 2800 on.
Low hanging fruit cardiac treaters.
Cardiologists Peter.
Yes, I think what we what we've talked about is.
You know thinking of a salesforce size somewhere around 100, plus or minus.
20 or so.
The plan is not to go after just the 2800 launch the plan is to go broader than that really kind of.
Optimized if you will see opportunity and going beyond that doesn't put enormous stressors strain on on the organization something we can manage I think.
Pretty easily.
With those types of numbers.
Great. Thanks for taking my question.
Thank you our next question comes from.
Credit Suisse. You May proceed with your question.
Hi, everyone. This is mark on from Marty. Thanks for taking my question I guess I was curious how should we interpret the each action 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 and injection fraction and then second did you observe any correlation between.
I mean objection fraction and diastolic function in the study thank you.
Okay.
Yeah, Hey, Mark I guess going back to pioneer pioneer was a dose ranging studies. So just keeping that in context that that's 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 dose.
It is which is what you see now and explore.
The so the reductions of ejection fraction that were let's say more than just a few percent were were driven by the dosing exploration that we did in the phase two.
Vice President to today, where we have you know 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 maintained safety, which is starting low end.
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 over.
Exposing mab account and to reduce yes unnecessarily difference there is the reduction any AFE on necessarily 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 yes, and these these folks are still above the normal range as you see any open label extension there in the high high Sixtys.
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 at really matter to manage safety and optimize.
Efficacy so even for those patients and 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 Peafiel to improve new your heart Association improved and that's all good stuff. So the only the only analog I will say is Maverick gave us the same low.
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.
Got it thank you.
Thank you our next question comes from.
You May proceed with your question.
Great. Thanks for taking my question I was just 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 explore 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 on recruiting into us explore thanks.
Yes, Sir Unexplored question, then Jay will take the valid question.
We haven't given a lot of details on the safety data that will present for explore at top line. I think you should expect us to provide customary topline safety data.
At that point, we're going to have all of it right when we get into the medical presentation, but for US you know the key things as it relates to safety that has to do with ejection fraction is really understanding the tolerability of the drug and and the if theres a persistent depression of ejection fraction below.
Normal in our clinical trials in both of our in all of our clinical trials the protocols set us a point at which it trigger some activity that point, we pick for explores 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 transients excursions below 50 will happen they will happen to folks without HCM and enough themselves. They are not a safety concern.
So for us putting those Ics reductions any have into the context of tolerability, particularly the most the most important to would be if you had people I'm ever canton for several weeks within ejection fraction that is below 40, you would expect then the hard to start behaving different.
It would react it would it would activate neural hormones that end up dilating to 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 its been a very very useful biomarker.
For us both on the safety and efficacy side up until this point because it does linked to.
Loosely links to contractility in 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 and potential adverse events related to heart failure.
Hope that helps.
Yes. Thank you.
And for about an hour valor complements what we're doing in explore it allows us to study patients now in the class four so to all symptomatic HCM patients patients on combination therapy completely exhausted their medical options and now are seeking.
Now an invasive procedure, either a supply reduction therapy by an open heart myomectomy or an alcohol septal ablation and so these data we think will really provide additional evidence to the impact of now the captain to provide important clinical benefits for our patients.
Great. Thank you.
Thank you. Our next question comes from Jeff along with Morgan Stanley You May proceed in your question.
Hi, This is head on for John Thank you for taking your questions.
Can you remind us how you're thinking about Q2 for a potential advantages it has ever matter Captain and then any aspect you'd highlight beyond the shorter housewife and then what are the gating factors to deciding if you'd partner in Europe. Thanks.
Okay.
Partnering and your upside.
I'll I'll give you a high level view on that but let me start with two to four so two to four you know when we started thinking about two to four as part of our strategy right. We are a disease focused company, we're not ill quote unquote asset driven we are looking at in the medium to long term to optimally manage people.
Who have HCM diagnosed 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 a new tool that we hope to introduce to their community to manage the diseases Mab accounting. Another one maybe two to four in the early days. So expect us to continue to research in other words HCM broadly to make sure that we are now.
Meeting our.
Our overall objective here, so more pipeline and more investment in research on that in the days before we got to the pioneer result, and certainly the open label extension result, with Napa Camden.
We were not entirely sure whether there was going to be an advantage.
Or a disadvantage to having a longer half life drug Maverick Hamptons 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 two to four was one where it has a similar activity profile, but has a shorter half life also as metabolize a little bit differently that could.
Could provide just.
Actual potential benefits.
Sitting here today Maverick Hampton looks really really good in fact 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 it's unclear to us whether a shorter half life drug in in of itself.
Would have a meaningful clinical differentiation or benefit.
There are some other aspects to two to four as we get the date as Taylor mentioned in the second half a year, we'll be able to speak more directly to this that could make it more appropriate for the 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 Maverick Hampton and if it does turn out that a profile of the drug like too.
Q4 has some advantages in certain situations, where we're right in position to really be able to take that forward.
Great. Thank on Europe, yes, so so Europe.
You know we're not we're not in any particular rush to partner in Europe. We're we've got the expertise within the company to understand how to get the right development program at a registrational package to support Europe. We also have with bill onboard and his team we've got.
Some folks in Europe in ahead.
Of our European and kind of.
Market now in place really learning at the local level and regional level.
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About the opportunity for Myokardia, so we'll be in a position to really assess whether where 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 would 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 explore was was a European and U.S. study. There we are understanding through our experiences with explore how patients are managed treated in flowed in Europe. So we've got a lot of experience on that and now already within the company.
Great. Thank you so much.
Thank you and as a reminder to ask a question you'll need to press star one on your telephone. Our next question comes from Mohit Bansal with City. You May proceed with your question.
Good afternoon, guys. This is Keith on from Mohit. Thanks for taking your questions. The first one is a from.
Valor could you characterize the risk benefit profile, you're seeing you're looking for in order to this plant SRT.
What's the bar, there I guess rather than noninferiority.
And then.
And for nine one.
In the phase two age just wanted to get a sense of how you're treating placebo effect given stable disease, there and if there's any implications for phase two trial design or endpoint. Thank you.
So for valor, we're looking to treat patients prior to a surgical or interventional procedure, rather than do 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 being able to avoid need for a procedure overall and we think that based on the parameters that we have seen out of pioneered what we expect out of explore we think that this will.
Benefit the vast majority patients who are being considered.
And I want to make sure I understand your foreign and one question do you mind sort of.
Given us another shot at it.
Sure sure. So the phase two a looks like was done in patients with stable heart failure, just wanted to get a sense of how you're looking at placebo effect, given the stable to Steve change over time.
Oh sure, yes, so I think going to stay in a interface to a study and Jay feel free to chime in here and at the placebo group gives you a lot of a lot of a 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 read outs. So with that in mine. It just gives us a lot more confidence in comfort that the signals in the trends that we're seeing a real.
And that we're starting to get a feel for during this period in time differences and Tolerability.
That's great. Thank you.
Thank you. Our next question comes from George Farmer with BMO. You May proceed in your question.
Yeah.
Hi, this is going on for George Good afternoon, everyone. Thanks for taking the question. The first one I guess is maybe a follow up from two of our colleagues who bought my thinking to lead the AMEA vessels.
Sort of combining the question, but for the upcoming Maverick presentation will there be any data on now the kimpton concentrations.
[noise] presented at that and will there be any data on ejection fraction.
Given the the Maverick trial is 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 explore a trial with the placebo response. So the 25% I think was from Liberty and I think it was mentioned, but Jay the 21% was the internal that you guys were seeing as this look.
At the.
Primary endpoint because the composite or are we looking more at the 1.5 proven Pico too with improvement in a way to my understanding was I haven't seen the end weighted data from Liberty trial. So the second part of the primary endpoint, which when there is no worsening and way check it may have been presented them we just.
But I just wanted to see if you guys can help understand that part of it. Thanks.
A golden I can hit the I can hit the second pretty quickly. It is it is a composite endpoint that drove the the the determination of the placebo effect. So for Maverick, it's the same composite.
For.
For Liberty, while they didn't collect New York Heart Association they collected.
Kansas City, Cardiome out, but the 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 PPL two is what's driving the placebo response in either kind of form of the definition of the composite primary endpoints. So very valid to look at both of those studies.
As appropriate analog is giving us confidence and explore.
Yes, and Maverick, yes, so we look going to talk about yes for sure and in fact, you know the the five patients that had per protocol.
Drug Discontinuations because they hit the 45, you should expect us to talk about them.
For the five of them.
That happened after increases in doses. So there will be more color around those cases and I just want to reiterate I think it was.
Basically I know palm 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 here that was the point much like we did in the phase two study with pioneer.
What is really critically important here is that so 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 you finding the the analog 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.
Full benefit with magic Hampton and not necessarily overexposing patients. So starting low adjusting based on something that is clinically connected to symptom improvement peak vo to 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 our FDA interaction, which we will not update who were not expecting to update you shouldn't expect us to update that HCC, we're going to come back later on with the input from FDIC and the go forward plan for non obstructed, but we can't tell you confidence now analyzing the maverick data that we're ready to dose.
Not affected patients with Mab accounting.
Thanks, Tom So that's really helpful.
Thank you. Our next question comes from David Nierengarten with Wedbush You May proceed with your question.
Hey, I just have one.
When you discuss the open label study or to open label extension.
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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 that but can you give any numbers on or percentages of patients go on the open label extension. Thanks.
Yes.
So let me start out the easy one is the great majority of our patients are actually rolling over into the LT.
Both out of exploring the vast majority of our Maverick patients did as well.
Patients choice to be able to do this and we know that they're doing a patients who have actually.
They have actually met stopping criteria as we discussed.
We are not included but we look forward to being able to get those folks into the program.
Soon.
Okay.
Thank you.
Thank you my next question.
Thank you. Our next question comes from Jim Birchenough.
Wells Fargo May proceed with your question.
Hi, guys I got dropped earlier so.
Policies up this was asked already but just on the Valor study could you maybe talk but what portion of the diagnosed patients with obstructive HCM are being considered or meet some criteria for steptoe ablation or my estimate and maybe remind us of what the echo criteria is for making that the.
Termination and what you would what level of reversal would you need to say you replace the need for for surgery, and then have a follow up.
So for a barrel or we look to what the guidelines.
Our HCC A.J. as well as ex us guidelines all call for.
You see 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 member camping will allow the vast majority of patients to be able to avoid need for this obviously, we're looking for something has to be durable result for these patients.
No for all of this is not a study where we can paramount the camp in person surgery, but we're looking to replace the need for surgery with most patients.
Is there an LTL t. gradient level that would qualify someone for surgery or is it based on symptoms and again.
Portion of patients are candidates for surgery.
So it's the same level of gradient that we have we explore trial over 50.
It is so that is based on the.
So echo gradient there and it's.
Presently is symptoms that are not really with present pharmacotherapy. So.
Many class two patients qualify as well as class three class four.
And then I think to it.
I was just going to say I think there is a 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 surgery 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.
Our our minimized.
To some extent, if you're at Mayo or at the Cleveland Clinic.
But every operative mortality for their 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 outline just line up and go get the surgery. So I think there about 1000 or so yes, I mean, when you would you consider all forms of septal reduction therapy, it's about 1500 50.
There are getting procedure, but I would estimate that it's a pretty significant multiples that are eligible dunkel onto.
And then maybe just.
One more question on hand, wringing around ejection fraction and maybe could speak to differences between the risk or Penn city to reduce injection fraction in an not obstructive setting versus obstructive setting if there's different dynamics at play where you might reasonably expect lower ejection fraction reduction.
And then one versus the other.
What we're seeing is a similar PD PK profile in both the non instructive in the instructive patients.
So.
Well, one can speculate differences there what we seems much more similarity.
Okay. Thanks for taking my questions.
Thanks, Jim.
Thank you and I'm not showing any further questions. At this time I would now like to turn the call back over to hospice Gianakakos for any further remarks.
Thanks, very much and thanks, everyone for all your questions. The team here and I really looking forward to keeping you updated on the continued progress with massive accounted in 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 it HCC the results of the Dent a captive studies.
A little bit later, and the topline explore read out 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.
Thank you ladies and gentlemen. This concludes today's conference call. Thank you for participating you may now disconnect.
Good bye.
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