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Edited Transcript of MYOK earnings conference call or presentation 9-May-19 8:30pm GMT

Q1 2019 MyoKardia Inc Earnings Call

SOUTH SAN FRANCISCO May 14, 2019 (Thomson StreetEvents) -- Edited Transcript of MyoKardia Inc earnings conference call or presentation Thursday, May 9, 2019 at 8:30:00pm GMT

TEXT version of Transcript

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Corporate Participants

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* Jay Edelberg

MyoKardia, Inc. - SVP of Clinical Development

* Marc Semigran

MyoKardia, Inc. - SVP of Medical Sciences

* Michelle Corral

MyoKardia, Inc. - Senior Director of Corporate Communications & IR

* Tassos Anastasios Gianakakos

MyoKardia, Inc. - President, CEO & Director

* Taylor C. Harris

MyoKardia, Inc. - CFO

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Conference Call Participants

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* Alethia Rene Young

Cantor Fitzgerald & Co., Research Division - Head of Healthcare Research

* Anupam Rama

JP Morgan Chase & Co, Research Division - VP and Analyst

* Hannah Lynne Latimer

Morgan Stanley, Research Division - Research Associate

* Mark William Connolly

Crédit Suisse AG, Research Division - Research Analyst

* Ritu Subhalaksmi Baral

Cowen and Company, LLC, Research Division - MD and Senior Biotechnology Analyst

* Tazeen Ahmad

BofA Merrill Lynch, Research Division - VP

* Yanan Zhu

Wells Fargo Securities, LLC, Research Division - Associate Analyst

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Presentation

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Operator [1]

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Good day, ladies and gentleman, and welcome to the MyoKardia First Quarter 2019 Financial Results Conference Call. (Operator Instructions) As a reminder, this conference call is being recorded. I would now like to introduce your host for today's conference, Ms. Michelle Corral. Ma'am, you may begin.

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Michelle Corral, MyoKardia, Inc. - Senior Director of Corporate Communications & IR [2]

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Thank you, Jimmy. Good afternoon, and thank you all for joining us for today's call. I'm Michelle Corral, MyoKardia's Head of Corporate Communications and Investor Relations. Today, we will be reviewing first quarter financial results and we're going to discuss recent corporate and clinical accomplishments, including the completion of enrollment in our MAVERICK Phase II of mavacamten in nonobstructive HCM.

Leading today's call is MyoKardia's CEO, Tassos Gianakakos. Tassos is joined by Jay Edelberg who joined MyoKardia last quarter from Sanofi as our SVP Clinical Development; Dr. Marc Semigran, SVP Medical Science; and Taylor Harris, our Chief Financial Officer.

A financial results press release was issued earlier this afternoon and is available on our website. As a reminder, the information discussed during this call will include forward-looking statements, which represent the company's view as of today, May 9, 2019. We undertake no obligation to update or revise any forward-looking statements to reflect new information or future events, except as required by law. Please refer to today's press release as well as our filings with the SEC for information concerning risk factors that could cause actual results to differ materially from those expressed or implied by these statements.

I'd like to now hand the call over to our CEO. Tassos?

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Tassos Anastasios Gianakakos, MyoKardia, Inc. - President, CEO & Director [3]

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Good afternoon, everyone, and thanks for joining us today. MyoKardia was founded with an important and bold vision: to overcome the challenges associated with cardiovascular drug development by bringing novel precision medicines to take on these diseases, simply not good enough to be treating millions of people with decades old nonspecific drugs. Instead of addressing everyone with heart disease as though it's a single common condition, MyoKardia researches the underlying causes of disease, designs a therapy specifically targeting the cause and identifies patients for whom that targeted medicine is most likely to benefit.

6.5 years into our journey, we've made remarkable progress. If we think about where we expect MyoKardia to be in just 12 to 18 months, we'll have mavacamten's new drug application approaching submission and review at the FDA for the treatment of obstructive HCM; a registration program in process in nonobstructive HCM, mavacamten's second indication; our candidate MYK-491 moving into late-stage development for the improvement of systolic disease; MYK-224 also moving into late-stage development for additional HCM segments, a fourth therapeutic candidate approaching the clinic and a growing preclinical pipeline based on our internal research platform.

It's a profile we're really excited to get to, 4 clinical programs: 3 in late-stage and 1 approaching commercialization. All of these therapies have been discovered and developed by MyoKardia's scientists. Our ambition is to be the world's leading cardiovascular company. We're focused on changing the lives of people with serious cardiovascular disease through bold innovation.

Our near-term path to achieve this is 2 main components: the first is realizing the full potential of mavacamten and the second is unlocking value from our growing pipeline. By achieving these 2 goals, we feel MyoKardia will bring much needed new therapies to people with HCM, systolic and diastolic disease, and in so doing create significant value for our stakeholders, including our valued employees and shareholders.

So let's take these 2 components one at a time, mavacamten first. What we're doing to realize this full potential. First, we're incredibly focused on the successful execution of our U.S. registration program for obstructive HCM. In parallel, we're ramping up our efforts to prepare for a successful U.S. launch and are evaluating a variety of options to get to patients outside the U.S. and around the world. We're also working hard to address additional patient segments that we think can benefit from mavacamten.

Along these lines, we announced today that we successfully wrapped up enrollment for MAVERICK, a huge achievement and key takeaway from today's call. MAVERICK is the largest study of its kind, looking at nonobstructive HCM. The study came in on schedule per our guidance, setting us up for top line results in the fourth quarter of this year, at which time we expect to advance into our registration program. Very proud of the team effort here.

And as we advance our clinical studies and get ready for mavacamten's potential commercial launch, we're building on our disease area leadership in several ways. We're deepening our relationships with the broader community diagnosing and caring for people with HCM, and we're working to increase awareness of the significant burden of disease and the need for additional new treatments. All of that positions us well to realize the full potential of mavacamten.

And our second objective of unlocking value in our pipeline, the current focus is on important value-creating catalyst for our 491 and 224 candidates. Specifically, we're generating important clinical data this year and are defining the target patient segments, we believe, they can benefit the most. While we won't spend too much time on that today, we will have more to say about them as we approach Phase II results for 491 later in the year and initiate Phase I with 224 in the coming months.

So the remainder of today's call will be focused on mavacamten and specifically on its potential to change the lives of people with nonobstructive HCM. With the imminent completion of MAVERICK's enrollment, Jay and Mark will walk you through the need for new treatments for nonobstructive HCM, why we believe mavacamten can be an important therapy in this disease and what we expect to see from MAVERICK study later this year.

Before I hand it over to them, a few updates relating to MyoKardia's commitment to disease area leadership and the great progress we're making in mavacamten's registrational program for obstructive HCM. We continue to be really pleased with the progress of the EXPLORER study. We're on track with enrollment, which we expect to complete in the second half of this year.

I recently hit the road with Jay and members of our clinical operations team for a week of EXPLORER site visits. For me, it was really gratifying to have the opportunity to see firsthand the hope and enthusiasm that's out there for mavacamten. These centers have been on the front line of HCM patient care for decades with limited treatment options, and they know firsthand the difficulties faced every day by people with this disease. Patients are out there and they're eagerly waiting for new treatments that can make a difference in their daily lives and can hopefully stave off the decline and complications that come over time with HCM.

These visits are incredibly inspirational. Not only does the close engagement with the sites help us ensure high-quality execution through training and monitoring, but it reminds us of the urgency and responsibility of our work. The growing enthusiasm we're seeing for mavacamten and EXPLORER was further fueled by the recent set of PIONEER-OLE data presented at the ACC this past March. That data from our PIONEER open-label extension continues to bear out the striking results we observed in Phase II, with the 9-month data recently accepted for presentation at the September European Society of Cardiology meeting in Paris.

Throughout MyoKardia's history, we've build relationships with the leaders in the field of HCM, from our founders to the share investigators, to the team at Duke that help develop the HCM Care App. That commitment continues with progress announced last week on 2 initiatives: MyoSeeds and 23andMe. MyoSeeds is a competitive research grant program funded by MyoKardia with the goal to encourage clinical and academic scientists to look hard at the underlying biology of cardiomyopathies. Three exciting projects have been selected for 2019, and we look forward to working with these talented scientists and supporting their important efforts.

Last week also saw the launch of the HCM community page, which will be available to an estimated 9,023 AMA customers, who have self-identified as having HCM. HCM is the most common inheritable cardiovascular disease. By partnering with a company like 23andMe focused on helping people access and understand their own genetic information, we can provide patients with important insights into their condition. In addition to being the right thing to do for the broader HCM community, these relationships support our programs as we look ahead to the potential approval of our products.

So at this point, I'm pleased to introduce you to Jay Edelberg, who will be providing the MAVERICK trial update. Jay joined us in February as our new Senior Vice President of Clinical Development, a clinical cardiologist and vascular biologist by training. Jay brings more than 20 years of experience from both academia and industry. He joined us from Sanofi where he led Global Cardiovascular Development and spearheaded the Praluent program through approval and launch. Jay also oversaw the clinical development and global project teams involved in the myocardial relationship while at Sanofi, and we're thrilled to have him on the team. Jay, take it away.

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Jay Edelberg, MyoKardia, Inc. - SVP of Clinical Development [4]

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Thanks, Tassos. It's been an honor and privilege to join the MyoKardia team, a team I've admired for several years, knowing their dedication to bring new therapies to our patients. As a cardiologist, I know the frustration and limitations my patients have with current treatments for cardiomyopathy and heart failure. I know we must do better. We know that the number of people suffering with heart failure in the U.S. will continue to grow and is projected to increase by over 30% in the next 10 years.

I believe we, at MyoKardia, have the opportunity to rewrite the fates of many of our patients by developing therapies, treating the specific molecular pathobiology that drive their condition. Our clinical development team is excellent and working well to deliver important studies for our patients. As Tassos mentioned, EXPLORER enrollment is on track and the trial is proceeding as planned. This is a notable achievement as EXPLORER is the largest and most comprehensive randomized clinical trial ever conducted in patients with obstructive HCM.

In MAVERICK, we're conducting one of the first and largest randomized clinical control trials in nonobstructive hypertrophic cardiomyopathy, or nHCM patients. MAVERICK is a dose-ranging study with a primary endpoint of safety and tolerability in the nonobstructive population. This groundbreaking trial promises to be highly informative and should establish the scientific foundation for registration program in nonHCM as mavacamten's second indication. The results should also provide clinical data on mavacamten's potential to impact patient's symptoms, heart function, including measures of diastolic compliance and relaxation. We are quickly approaching complete enrollment in MAVERICK, having closed screening on schedule on April 19. The last patient should enter the study enrollment next week.

Patients in MAVERICK have been assigned to one of three groups. To receive once daily doses of mavacamten, targeting two dosing concentrations centered around 200 and 500 nanograms per mL or placebo. By design, some patients will be above and others below the target concentrations in order to get a fuller picture of the most clinically appropriate dosing approach in this population since there is no obstructive gradient to guide dose titration.

And our patients started on a low dose. And after PK assessment at week 4, doses are adjusted in the blinded fashion at week 6 in line with the patient's assigned cohort. Patients in MAVERICK may remain on any background medications during the duration of the study. The duration of MAVERICK is 28 weeks, including a 4-week screening period, 16 weeks on treatment and additional 8 weeks for wash out. Following the trial period, MAVERICK patients are eligible and encouraged to participate in the ongoing MAVA long-term extension study. Top line results from MAVERICK are anticipated in the fourth quarter of this year.

Keeping in mind the trailblazing nature of this trial in this population, success in MAVERICK is primarily about establishing drug safety and defining the protocol parameters for registration program in nHCM. In addition to safety and dosing, we'll also be looking for trends and symptoms and functional improvements, indications of mavacamten's effects on diastolic compliance.

I should note that MAVERICK is not designed to achieve statistical significance in these endpoints. Among the secondary and exploratory endpoints that will be assessed mavacamten include exercise capacity as measured by peak VO2, changes in New York Heart Association Functional Class and diastolic and systolic function as measured by echocardiography, plasma NT-proBNP levels and symptoms and quality of life assessments. We have even integrated a digital health component into the study to track patients' day-to-day activities using wrist-worn accelerometer.

Based on MAVERICK, we anticipate identifying dose, duration, population or subpopulation and the clinical endpoints, much the same way that we did the totality of the data from the 2 cohorts of PIONEER that guided the design of EXPLORER.

A second aspect of MAVERICK will be very meaningful to us as we can learn about mavacamten's impact on diastolic compliance. Considering the recent data from PIONEER-OLE, the context of MAVERICK, we're particularly excited about the potential translation to the nHCM heart. The first I'd like to highlight is NT-proBNP, a well-established measure of cardiac wall stress. In OLE, we saw levels go from a mean of over 1,800 down to 170 picograms per mL, a greater than 90% reduction. I also want to highlight the reduction in left atrial volume seen in PIONEER-OLE. We know that elevations in LA volume is an indicator of potential diminished cardiac function, increased risk of heart failure, stroke and death.

Most specifically, LA volume is a predictor of atrial fibrillation in HCM patients. In the OLE, we saw statistically significant decrease in LA volume from just over 40 milliliters per meter squared to less than 30 at week 24. We look forward to seeing the results of LA volume in MAVERICK. The results of MAVERICK have the potential to propel us into a late-stage efficacy studies, a mavacamten's second indication. Similarly, the results will provide important insights that will be applied to our research programs. Ultimately, data generated from the study will be meaningful in fueling our future pipeline growth. We anticipate reporting top line data from MAVERICK in the fourth quarter, and we'll pursue presentations of the data at medical and scientific congresses early next year.

Marc will now talk about the needs in HCM patients. Marc, take it away.

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Marc Semigran, MyoKardia, Inc. - SVP of Medical Sciences [5]

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Thank you, Jay. I wanted to take a moment today to review what we know about nonobstructive HCM and why we are all so excited for the data that will emerge from the MAVERICK trial. The nonobstructive HCM population makes up approximately 1/3 of HCM patients. Based on our analyses of claims data and the literature, there are approximately 30,000 to 40,000 nHCM patients in the U.S. diagnosed and seeking treatment. In addition, there is ample evidence that there are both nonobstructive and nonobstructive HCM are greatly underdiagnosed.

Nonobstructive HCM patients share the same genetic mutations observed in obstructive HCM. The mutations have the same primary effect; increasing contractility of the heart, which in turn results in abnormally thick heart muscle tissue that is stiff and noncompliant; cardiac filling and pumping with each heartbeat is diminished, even as the disease causes the heart to work harder. Patients with nonobstructive disease suffer from shortness of breath and a feeling of tightness and congestion in their chest that limits activity.

Nonobstructive HCM patients are also highly prone to develop atrial fibrillation, stroke and heart failure. There are no targeted therapeutic treatment options available to nonobstructive HCM patients. At Mass General, where I led the heart failure and cardiac transplant program, we implanted left ventricular assist devices, or LVADs, in patients with advanced nonobstructive HCM to assist their heart in pumping blood and keeping them alive until a donor organ was available for a heart transplant.

While both LVAD implantation and transplant can be lifesaving, they are complex surgical procedures that do result in a limited quantity and quality of life. The defining difference between nonobstructive HCM and obstructive HCM is, of course, the lack of obstruction of the left ventricular outflow tract. In obstructive HCM, the heart muscle thickening is more marked in the intraventricular septum, while in nonobstructive HCM, the thickening is symmetric. In comparison with an obstructive HCM patient, a nonobstructive patient's heart suffers more from severe abnormalities of diastolic relaxation and compliance as the left ventricle's ability to relax and fill with the oxygenated blood is eliminated and the heart is unable to nourish itself and meet the needs of the rest of the body.

The mutations underpinning both obstructive and nonobstructive HCM cause too many myosin heads to be engaged in what we call the dynamic state and this generates excessive force in the heart muscle. In a normal person at rest, only about 18% of cardiac myosin is in this dynamic state and available to bind with actin. While the majority of myosin heads are in a quiescent state and stay in reserve until needed.

In the HCM heart, studies from our research lab have observed that the number of myosin heads in the dynamic state is almost twice normal. At a molecular level, this is just the heart is working and so we are running a sprint all of the time. Mavacamten acts by correcting this imbalance between the dynamic and quiescent state of myosin.

In other studies, it has been demonstrated that myosin modulation appears to normalize systolic contractility and improve diastolic relaxation, compliance and filling in animals and patients. You may recall at last November's AHA, we showed using invasive pressure volume loops that mavacamten treatment of mini pigs with genetic nonobstructive HCM improved diastolic compliance. At the same AHA meeting, Dr. Steve Heitner of Oregon Health Sciences University and an investigator on our Phase II PIONEER study presented clinical data showing that mavacamten treatment improved to establish noninvasive echocardiographic biomarkers of diastolic function. These improvements with mavacamten occurred in measures of LV relaxation, diastolic filling pressure and end diastolic volume.

Looking closely at the changes from baseline in other measures of diastolic function, such as left atrial volume, NT-proBNP and E/e' prime in the PIONEER open-label extension, we continue to see encouraging evidence of a return towards normal.

And as we get closer to MAVERICK readout near the end of this year, we are optimistic that we will continue to see evidence in the exploratory echocardiographic and plasma biomarker endpoints of mavacamten's ability to improve diastolic function.

The ability to improve compliance and relaxation of the heart during diastole would not only be meaningful in the treatment of nonobstructive HCM, but it could ultimately be one of the most important discoveries we make at MyoKardia, opening up the possibility of treating segments of the 3 million patients in the U.S. who suffer from heart failure driven by the diseases of diastolic dysfunction.

We believe that within this huge heterogeneous patient population, there are distinct groups of patients for whom distinct etiologies lead to the heart failure syndrome. For those who disease is driven by defects in the heart's contraction and relaxation mechanisms, new classes of compounds like mavacamten and our discovery stage LUS-1 program could transform their care. I'm, as I know my colleagues are, incredibly excited by the opportunity that lies before for us to take a leading position in transforming the landscape of heart failure care using a precision medicine approach to tackle one disease at a time.

Taylor will now talk through the quarter's financial results.

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Taylor C. Harris, MyoKardia, Inc. - CFO [6]

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Thanks, Marc. I'll start with a few highlights from our first quarter 2019 results. Total operating expenses were approximately $40 million, including $26.2 million of R&D and $13.6 million of G&A expense. This reflects a year-over-year increase of approximately $16 million, driven by R&D spend, reflecting the advancement of mavacamten into late-stage studies, including MAVERICK, EXPLORER and MAVA-LTE.

Our Q1 R&D expense was net of approximately $10 million of reimbursement from Sanofi. And as a reminder, our collaboration agreement with Sanofi formally concluded at the end of the first quarter. And Q2 will be our final quarter to receive reimbursement related to the mavacamten program.

As such, operating expenses in the second half of the year will trend upward due to the lack of R&D credits combined with continued pipeline development. We ended the first quarter of 2019 with $628 million in cash and investments, up from $395 million at year-end. The increase was driven by net proceeds from our follow-on offering at the end of March. We're now funded into the second half of 2021 more than a year past the expected top line data from EXPLORER. Included in our runway projection is the full registration program for mavacamten and obstructive HCM and the ability to aggressively advance our pipeline into later stages of development following anticipated positive milestones later this year. We're grateful for the strong support demonstrated by both our existing and new investors. And you have our commitment to use the funds wisely and efficiently.

So far in 2019, we've hit one major milestone with the release of our 6-month PIONEER-OLE data and we're close on the second key milestone with the imminent completion of enrollment in our MAVERICK study. Our productivity and execution against our goals will continue. Later this year, we'll be wrapping up enrollment in our pivotal EXPLORER study, reporting data from MAVERICK as well as additional longer-term data from PIONEER-OLE. In our MYK-491 program, we will be presenting data from the Phase Ia study later this month at ESC Heart Failure. And in the second half of the year, we'll provide a top line readout from the ongoing Phase II study. And lastly, our third clinical candidate MYK-224 will be advancing into Phase I studies midyear.

So with that, I'd now like to open the call up to questions. As a reminder, here with me and Tassos are Dr. Jay Edelberg and Dr. Marc Semigran.

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Questions and Answers

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Operator [1]

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(Operator Instructions) Our first question comes from Tazeen Ahmad with Bank of America.

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Tazeen Ahmad, BofA Merrill Lynch, Research Division - VP [2]

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I just wanted to get a comparison of how you think of the market opportunities differ between the obstructive HCM and the nonobstructive market? I know that obstructive is larger, but can you give us a sense directionally about size?

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Tassos Anastasios Gianakakos, MyoKardia, Inc. - President, CEO & Director [3]

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Yes, if we -- Tazeen, thanks for joining our call. If we look at the U.S. for a minute, and I think globally we can -- we've got some good evidence that about 1 in 500 people around the world plus or minus in certain regions are carriers of a pathogenic mutation that leads to HCM. So in the U.S., that translates to about 600,000 or 700,000 people, 2/3 of those folks will be obstructed and 1/3 nonobstructed. But of that population today, a 15% of them only, so around 100,000 or so are seeking medical attention and we can track them through insurance claims in the system.

So if we think about the current state of the situation where the diagnosis rate is still relatively low and assume for a minute that that's going to be the context in which we launch into for the U.S. at least, we think about 100,000-or-so patients for HCM as a product addressing both obstructive and nonobstructive was about twice as many obstructive patients that could potentially benefit. We are working hard on things like you're seeing with 23andME and our share registry and other efforts to increase awareness, and I think between those and the introduction of mavacamten, if approved, we're hopeful that we'll see an increase in the diagnosis rate as well.

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Tazeen Ahmad, BofA Merrill Lynch, Research Division - VP [4]

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Okay. Tassos, and then how are you thinking about the size of the sales force that would be needed once you become commercial?

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Tassos Anastasios Gianakakos, MyoKardia, Inc. - President, CEO & Director [5]

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Yes. That is generally I can tell you, it is a very focused set of cardiologists today who are treating these folks in the U.S. and in Europe. So these are generally split between about in the U.S. maybe 40% or 50% tertiary centers of excellence, where they are really focused on heritable cardiomyopathies and HCM. And then there are some patients who are cared for and roughly a couple of thousand or so additional cardiologists who are outside of those specialty centers. So that is very much a focused effort for us. I think in the order of 100 or so, plus or minus, reps but very much in the, I would say, orphan kind of commercial model.

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Tazeen Ahmad, BofA Merrill Lynch, Research Division - VP [6]

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Okay. And then maybe the last question from me. In terms of which patients in this population you would think would be most amenable to your therapy? Would you say it's the entire adjustable population or a certain subset?

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Tassos Anastasios Gianakakos, MyoKardia, Inc. - President, CEO & Director [7]

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Well, I think to the extent that these are patients who suffer from symptoms, which for most of them who are seeking medical attention, they have some sort of functional or symptomatic limitation. The evidence that we're generating so far is telling us that we're improving people symptoms and function. So that bears out, that gives us an opportunity to really help those folks.

If we're able to start seeing more benefits that are longer term and involve the interruption or the change in the disease process, which we are getting some evidence from the open-label extension on, I think that just makes it that much more valuable and that much more exciting for physicians to really get their patients on this therapy earlier, particularly for those ones that have had disease and have suffered with some of the more complicated aspects of the disease like atrial fibrillation and a little bit further downstream. Yes, Marc, please add.

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Marc Semigran, MyoKardia, Inc. - SVP of Medical Sciences [8]

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Yes. I mean just answering, so -- I mean we've talked a lot in the past about that some patients with obstructive disease do respond to beta blockers. There were no targeted therapies for the nonobstructive patients. I mean Beta blockers, you can't even hardly make a case physiologically why they would work and the experience of clinicians is that in fact they don't work. So I think that for symptomatic nonobstructive HCM that MAVA is going to be the way to go.

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Operator [9]

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And our next question comes from Jeff Hung with Morgan Stanley.

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Hannah Lynne Latimer, Morgan Stanley, Research Division - Research Associate [10]

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This is Hannah on for Jeff. We were wondering for the PIONEER open-label data later this year, do you expect to report largely the same aspects as you did with the 6 months data? And are there any other additional aspects of the data that you think we should be focusing on?

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Jay Edelberg, MyoKardia, Inc. - SVP of Clinical Development [11]

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So this is Jay. I think that you will be wanting to focus down on how durable those benefits are as the PIONEER-OLE continues to progress and really want to call attention to the sustained improvements in New York Heart Association class, the sustained reduction in gradient and, of course, the sustained reduction in NT-proBNP. And as I mentioned, very exciting to see the impact of the reduction in left atrial volume size.

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Hannah Lynne Latimer, Morgan Stanley, Research Division - Research Associate [12]

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And then just one more, if I can. On the DCM data later this year, what do you expect to report for that? And what do you see as the bar for deciding whether to advance the program or not?

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Tassos Anastasios Gianakakos, MyoKardia, Inc. - President, CEO & Director [13]

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Yes. That's a program we're excited about. We're so far in Phase I. We've shared some single-dose data in healthy volunteers and in people who have reduced systolic function. And what we're seeing in those single-dose studies really well-tolerated range of doses, which is first and foremost what we're looking for in the Phase I program. So keep a close eye out on tolerability and safety.

We're also seeing improvements in some hemodynamic parameters, importantly looking at increasing stroke volume, which is the amount of the volume of blood that's ejected with every systolic squeeze of the heart. We are seeing in single doses a stroke volume improvements of 10% to 15%. And a 10% improvement in stroke volume for us that's well tolerated in this multiple ascending dose study will be pretty exciting. So similar results as what we've seen so far in the single doses is really what we're really looking for.

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Operator [14]

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Our next question comes from Ritu Baral with Cowen.

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Ritu Subhalaksmi Baral, Cowen and Company, LLC, Research Division - MD and Senior Biotechnology Analyst [15]

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Just a few on MAVERICK conduct now that the trial is fully enrolled or close to. Can you tell us how many DSMB looks -- safety looks you've had during that trial if they're looking at ejection fraction reductions? And how overall trial conduct has gone with like dropouts and compliance, et cetera?

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Tassos Anastasios Gianakakos, MyoKardia, Inc. - President, CEO & Director [16]

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Ritu, it's Tassos here. So we're not going to get into some of the specifics that you're asking for at this point, but what we can tell you is very pleased and excited enthusiastic about the progress of the study so far. We look at things along a couple of dimensions, not just the enrollment rate, but really who are the patients that are coming in, we assess that; the quality of the data that we're collecting, we continuously asses that as well. So in terms of the various facets, we're really happy with where we're at.

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Ritu Subhalaksmi Baral, Cowen and Company, LLC, Research Division - MD and Senior Biotechnology Analyst [17]

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Got it. And I just wanted a clarification of one of your comments, Marc. Maybe I misheard this, but you said that the MAVERICK was designed with 3 cohorts, 2 target doses. And did I hear you right, you said it was designed so that some patients achieved or stabilized at above and below the 200-nanogram per mL and 400-nanogram per mL target. How -- if that's the case, how do you -- like what's the protocol there?

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Jay Edelberg, MyoKardia, Inc. - SVP of Clinical Development [18]

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Yes. So we have 3 different cohorts. There are some patients where we're targeting to get around 200-nanogram per mL or picogram per mL, others where we're are looking at 500. And so therefore, we expect there obviously going to be a range in the overall final. So this actually gives us that fuller range so we can actually design a registration program around the right dosing regimen for our patients.

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Ritu Subhalaksmi Baral, Cowen and Company, LLC, Research Division - MD and Senior Biotechnology Analyst [19]

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So you're not titrating tightly to either 200 or 500, there's going to be some variability in that range?

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Jay Edelberg, MyoKardia, Inc. - SVP of Clinical Development [20]

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It's actually built in to make sure that we get that full range of PK because we need to know that information so we can design the best registration program.

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Ritu Subhalaksmi Baral, Cowen and Company, LLC, Research Division - MD and Senior Biotechnology Analyst [21]

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Okay. And so I guess, will patients sort of evenly -- be evenly distributed in this range? Or there are other...

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Jay Edelberg, MyoKardia, Inc. - SVP of Clinical Development [22]

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The cohorts are 1:1:1.

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Ritu Subhalaksmi Baral, Cowen and Company, LLC, Research Division - MD and Senior Biotechnology Analyst [23]

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Okay. Got it. Okay. And then you talked about the differences between obstructive and nonobstructive and how -- basically the main difference is obviously the hypertrophy, the symmetric versus the nonsymmetric hypertrophy centrally. Is there any difference in symptom profile between obstructive and nonobstructive? Is there any differences between, I guess, the severity of dyspnea or the rate of dyspnea and any of the other functional measures?

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Jay Edelberg, MyoKardia, Inc. - SVP of Clinical Development [24]

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So patients with both obstructive as well as nonobstructive hypertrophic cardiomyopathy are symptom limited. They received reductions in New York Heart Association class, reductions in exercise capacity, increased rates of atrial fibrillation, et cetera. So we're focusing on those patients who have -- who are limited. And we're able to use the baseline characteristics of PIONEER to identify profiles of patients where we thought that we would actually get the maximum benefit for our patients.

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Ritu Subhalaksmi Baral, Cowen and Company, LLC, Research Division - MD and Senior Biotechnology Analyst [25]

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Got it. But the overall population is dyspnea, is it more severe in these patients? Is it less severe? Are there other sort of types of symptomology differences between the 2 population?

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Marc Semigran, MyoKardia, Inc. - SVP of Medical Sciences [26]

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Yes. So there are 2. I mean so syncope, loss of consciousness is more common in the obstructive patients. And the anginal chest pain related to ischemia is more common in the obstructive patients. But I agree Jay, I mean in terms of our target endpoints exercise capacity limitations as we assess with peak oxygen consumption and functional capacity in New York Heart Association, those are strikingly similar between the 2 groups of symptomatic patients.

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Operator [27]

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Our next question comes from Anupam Rama with JPMorgan.

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Anupam Rama, JP Morgan Chase & Co, Research Division - VP and Analyst [28]

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Congrats on all the progress. Maybe a quick question for Taylor. You noted that the cash was good until the second half of 2021 and you made some broad comments about the assumptions on the pipeline, but maybe what specifically is assumed in the guidance for development plans for MYK-491?

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Taylor C. Harris, MyoKardia, Inc. - CFO [29]

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Sure. Yes. So as we mentioned we've got the full registration program for mavacamten in obstructive. We've also built in assumptions for what we're going to move to after MAVERICK in nonobstructive. So I think mavacamten, you probably got a pretty good idea there and that really is to support the comment Tassos made, which is a key strategic goal here is to realize the full benefit of mavacamten. So there's a lot we're doing both in terms of clinical development as well as other HCM community building initiatives to make sure that we're exploiting the full value and delivering the full value of mavacamten. But then also and this is really what our recent follow-on offering allowed us to do is to have some good options on where we take other programs once we get to some of these milestones later in the year.

So specifically with MYK-491, we do have the option and we've built this into our cash guidance to move into some potential proof-of-concept studies in targeted patient populations. And that's what the team is really working up right now so that when we get to later this year to a point where we're able to show the data from the current Phase II, we can not only show data but also talk about potential next steps from there. But we do have that option built into the cash runway.

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Operator [30]

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And our next question comes from Martin Auster with Crédit Suisse.

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Mark William Connolly, Crédit Suisse AG, Research Division - Research Analyst [31]

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This is Mark on for Marty. I guess first, when talking to experts they mentioned that the VO2 improvements in PIONEER maybe driven by both change in diastolic function and gradient improvement. How should we think about the respective degree of benefit from each of these components?

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Jay Edelberg, MyoKardia, Inc. - SVP of Clinical Development [32]

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So I think you need to take a look at this holistically. These hearts are severely impacted of obstructive diastolic components as well. And what we're seeing overall is a significant improvement in the reduction in the gradients, the improvements in peak VO2, the reduction in symptoms. So we think that actually this is fully integrated and one isn't going to simply separate out one from the other because of the interrelationship.

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Tassos Anastasios Gianakakos, MyoKardia, Inc. - President, CEO & Director [33]

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I would just add there, Mark, too. What we're seeing now both in people and in animal models like pigs and we've published some of this data is real improvements in diastolic compliance. I mean this is remarkable, right? And it's -- there haven't been drugs out there that have done this. That is lowering filling pressure. That's increasing filling volumes. That is very likely, if it persists, to help people feel better and do more. So we don't want to underestimate the value and the potential impact on symptoms and functions that a drug like mavacamten that improves diastole can potentially have if we see this data pan out in the nonobstructive population and in future time points of the open-label extension.

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Mark William Connolly, Crédit Suisse AG, Research Division - Research Analyst [34]

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Got it. And then can you compare the baseline peak VO2 in MAVERICK or expected baseline peak VO2 in MAVERICK versus PIONEER?

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Jay Edelberg, MyoKardia, Inc. - SVP of Clinical Development [35]

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So we're targeting very similar baseline demographics.

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Operator [36]

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And our next question comes from Alethia Young with Cantor Fitzgerald.

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Alethia Rene Young, Cantor Fitzgerald & Co., Research Division - Head of Healthcare Research [37]

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I just want to talk a little bit about -- I know there's some meta-analysis on long-term outcomes from nonobstructive, which kind of suggests over the longer-term that maybe there is not much risk of cardiac death and event. Do you think there's any kind of sensitivity that profile when you think about regulatory pathway, thinking about what studies are next? Or do you think the pathway is more similar to like what is with obstructive where I think the evidence seems a little more straightforward?

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Tassos Anastasios Gianakakos, MyoKardia, Inc. - President, CEO & Director [38]

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Yes. I think, Jay, can chime in, in a second here, but I do think Alethia that the regulatory pathway and the conversations are likely going to be similar in terms of the evidence hurdles for safety, the evidence hurdles for efficacy. Right now, we're looking at improvements in function and in symptoms for FDA registration, but very exciting for us and certainly a big part of the story is how we can effect disease burden beyond those.

Those are of really important. They're going to impact if we're able to support those at registration, those 2 facets, they're going to impact quality of life improvements and day-to-day improvements. But if we can also demonstrate some of the things we're now seeing in that open-label extension, reductions in NT-proBNP, reductions in LA volume, et cetera, it's going to be really exciting. Our view is those are not necessarily going to be regulatory requirements to prove in either subset, but nevertheless they're important for us and as you know we're really going after them.

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Alethia Rene Young, Cantor Fitzgerald & Co., Research Division - Head of Healthcare Research [39]

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And Jay, any comment on my kind of outcome studies that exists like there's some particular bias to think about?

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Jay Edelberg, MyoKardia, Inc. - SVP of Clinical Development [40]

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Well, remember, the patients that we're trying -- that we're studying in MAVERICK are impacted. They have symptoms. They have functional limitations and we're looking to improve that overall. And so we're expecting that based on positive results here, we'll be able to identify the right type of functional symptomatic endpoints, much the way that we were able to identify those coming out of PIONEER that would allow us to pursue a registration program.

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Operator [41]

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And our next question comes from Jim Birchenough with Wells Fargo Securities.

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Yanan Zhu, Wells Fargo Securities, LLC, Research Division - Associate Analyst [42]

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This is Yanan dialing in for Jim. So first question, ejection fraction is something you looked at from a safety perspective in the obstructive HCM study. So just wondering from the nonobstructive HCM side, is ejection fraction of similar importance safety-wise or less importance or more importance, could you comment on that?

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Jay Edelberg, MyoKardia, Inc. - SVP of Clinical Development [43]

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Yes. Monitoring the effects on ejection fraction are important in both the obstructive as well as the nonobstructive patients and that's why we're studying the range of different PK doses there so we could identify the right dosing regimen that we can take forward into our registration program in the nonHCM patients, much the way that we've identified dosing regimen that we're testing now in the EXPLORER trial.

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Yanan Zhu, Wells Fargo Securities, LLC, Research Division - Associate Analyst [44]

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Great. And then so you're also thinking from the obstructive HCM side. You had success in using imaging of the gradient as a method to guide dosing. So for the nonobstructive, I know there is no imaging that's probably validated for outcome. But do you think with your data from MAVERICK, could you identify potentially imaging parameters like LV volume or diastolic compliance that you can then use in the future pivotal study to guide dosing or to help in some way?

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Jay Edelberg, MyoKardia, Inc. - SVP of Clinical Development [45]

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We're really going to be looking at all the parameters of LV function and symptomology and functional improvement to help us to be able to guide both what the dosing regiment and the endpoints that we'll be monitoring going forward will be. So I think that we know that this is a -- basically a Phase II trial that allows us to identify these trends, it will allow us to identify what's right for registration program.

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Yanan Zhu, Wells Fargo Securities, LLC, Research Division - Associate Analyst [46]

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Got it. And then last question. I know you are running the MAVA-LTE study, which enrolls in open-label fashion people -- patient from EXPLORER as well as from MAVERICK. So the question is would it be possible that you might readout MAVA-LTE at some point because the study is open-label and give us a clue about what treatment effect we should expect for the -- either the Phase III EXPLORER or the Phase II MAVERICK?

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Jay Edelberg, MyoKardia, Inc. - SVP of Clinical Development [47]

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Yes. We're looking forward to the results of MAVERICK that will have the top line results from later on this year. The long-term extension obviously is populating if the patients come out. And then next year, we're looking forward to the results of EXPLORER and looking at the totality of all of these data together.

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Operator [48]

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

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Tassos Anastasios Gianakakos, MyoKardia, Inc. - President, CEO & Director [49]

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Thanks, Jimmy. MyoKardia has an incredible opportunity to make a big difference in the lives of people with diseases of the heart muscle, starting with HCM. Our commitment is to advance the understanding of these diseases and better support the patients, their families and the physicians and staff who care for them.

HCM continues to be misunderstood and underdiagnosed. There is inadequate treatment options available today. It is a progressive severely debilitating disease that robs people all of their ability to enjoy the simple activities of daily living and puts them at risk of serious or even fatal complications. What we're learning from the patients who so generally share their stories with us is that each of them face unique challenges and questions and managing life with this chronic condition.

One thing we do see with remarkable consistency is their strength. They deserve our best efforts and we're giving it to them, embracing a bold and expansive vision of MyoKardia of how we can change their lives for the better. It starts with bringing forward our first precision cardiovascular therapy through registration and commercialization, accompanied by a deep pipeline addressing HCM, diseases of systolic function and tackling the challenges of diastolic disease. This will involve continued progress, successful program execution and growing momentum, which I look forward to sharing with you along the way.

As always, we're very grateful to the patients who participate in our studies, the investigators whose mission we share, to our shareholders who's support of our mission enables our important work and to our dedicated employees who are responsible for all our achievements. Thanks to everyone for your time today and for your continued support of MyoKardia and our mission.

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Operator [50]

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Ladies and gentlemen, thank you for your participation in today's conference. This does conclude your program. And you may all disconnect. Everyone, have a great day.