Braveheart Bio, Inc. (BRVE) Earnings Call Transcript & Summary

Welcome to the Braveheart Bio call today. My name is Josh, and I will be your operator for today's call. [Operator Instructions] Please note that this conference call is being recorded. I will now turn the call over to Paul Rickey, Chief Financial Officer at Braveheart. Paul, you may begin.

Thank you, Josh. Good afternoon, and thank you all for joining us. Before we begin, I'd like to remind you that today's remarks contain forward-looking statements. Please refer to the risk factors in our most recent filings with the SEC for a discussion of the factors that could cause actual results to differ materially from what you will -- what we will cover in today's discussion. Earlier this afternoon, we, along with our partner, Hengrui, presented data from our BHB-1893 program at the American Heart Association Scientific Sessions 2026. A press release describing these results as well as the presentations themselves are available on our website at braveheart.bio. With us today, we are pleased to have Dr. Anjali Owens, Associate Professor of Medicine at the Pearlman School of Medicine at the University of Pennsylvania. Dr. Owens is also Medical Director, Penn Center for Inherited Cardiovascular Disease. Also joining us is Dr. Marko Harper, of Virginia Mason Franciscan Health, where she is the Medical Director of Hypertrophic Cardiomyopathy Center of Excellence. To begin, we'll have Dr. Travis Murdoch, our Chief Executive Officer and Board Director, share an update.

Thank you, everyone, for spending time with us today. We are a late-stage clinical biotechnology company focused on developing BHB-1893 to improve the lives of patients with HCM and related conditions. We believe that our therapeutic candidate, BHB-1893, has differentiated potential in HCM across efficacy, safety and ease of use. We plan on sharing with you today further data that reinforces this profile, but also guides our development plan to further develop a preferred treatment option for patients. We are advancing global Phase III development in both forms of HCM. In obstructive HCM, we have initiated Lionheart-HCM, which aims to demonstrate the efficacy and safety of BHB-1893 head-to-head with beta blockers. -- with an option for single titration at week 4. In addition, we have a fully enrolled study on top of standard of care that is being conducted by our partner, Hengrui, and from which we expect data next year. Today, we will introduce Trueheart-HCM, which plans a fixed dose design and which we believe could be an important opportunity to expand the reach and simplicity of BHB-1893. We have received supportive regulatory feedback on this approach and plan to initiate the study in the first half of 2027. In nonobstructive HCM, we are in midst of initiating Noble Heart, which is a placebo-controlled study of BHB-1893. Today's focus is on the newly presented clinical and mechanistic data and how they inform our clinical development plan. We believe that our differentiated pharmacology could result in best-in-disease potential across both obstructive and nonobstructive HCM, which we plan to confirm across the studies outlined in the prior slide. We believe this is supported by the robust data presented today now with 1-year follow-up in obstructive HCM in addition to the NHCM shared data shared prior this year. We believe that in totality, the pharmacologic and clinical profile of BHP1893 provides an opportunity to drive differentiated efficacy and safety while providing a highly simplified dosing regimen that could expand access to patients with HCM. I'd now like to pass it over to Dr. Marko Harper, who will provide an overview of HCM and the current treatment landscape. Dr. Harper?

Thank you, Dr. Murdoch. So HCM or hypertrophic cardiomyopathy is the most common inherited cardiac disease worldwide, and it continues to have a significant unmet need. HCM is defined by asymmetric left ventricular hypertrophy with an end diastolic wall thickness of greater than or equal to 15 millimeters or greater than or equal to 13 millimeters in adults with a family history of hypertrophic cardiomyopathy or a positive genetic test. This is in the absence of another identifiable cause of LDH that explains the full magnitude, although concurrent conditions such as hypertension and aortic stenosis are common. HCM is classified into obstructive and nonobstructive HCM based on the presence or absence of left ventricular obstruction. As you can see on the left is your healthy heart and the big difference between the OPM and APM is the presence of a less ventricular alpha obstruction that can be at rest or dynamic and the magnitude is greater than or equal to 30 millimeters of [indiscernible]. But regardless of obstruction, there is a commonality of thickening a small LV chamber, a hyperdynamic ejection fraction. It is a period in lifelong progressive cardiovascular disease with the underlying disease burden made up of diastolic dysfunction with impaired myocardial relaxation, elevated LV fitness and frequently increased LV filling pressures. There can be ongoing cardiac damage due to chronic myocardial stress and this often results in an elevated biomarkers such as troponin. The long-term myocardial injury and myocardial ischemia can lead to fibrosis and scarring in a majority of patients. The symptoms are often heterogeneous that can cause significant patient limitations, including certain suppress -- chest tightness or chest pain and fatigue, all of which are worked with exertion and there can be the presence of near syncope and syncope, both with activity or sometimes even at rest due to a rhythmic potential. The risks with hypertrophic cardiomyopathy overall lifetime include an increased burden of [indiscernible] who may be affected with hypertrophic cardiomyopathy, many who may not know that they are at risk of developing this condition. The point prevalence is somewhere between about 100 and 200 to 1 in 500 patients, and once the patient develops obstructive hypertrophic cardiomyopathy, there is a significant burden on health systems and patient quality of [indiscernible], and the OEM can often increase the risk of the comorbid condition and the reason for hospitalization. Ultimately, this is a lifelong chronic condition that requires management and ongoing therapy. Cardiac myosin inhibitors target the root cause of disease in obstructive hypertrophic cardiomyopathy. For the AHA/ACC 2024 guidelines, first-line therapies are still recommended in these influence beta blockers, nondihydropyridine calcium channel blockers. And these are really targeting the symptoms, but there's limited HCM trial evidence for effect and long-term benefit and disease modification. Septal reduction therapy is also recommended in the subset of patients who have severe limiting systems and severe gradients who have failed for line therapy, but they require an experience center with experienced high-volume surgical expertise. Cardiac myosin inhibitors were introduced and recommended in the guidelines in 2024, and they really do target the underlying pathophysiology of obstructive HCM. Cardiac myosin inhibitors treat the HCM at the level of the cardiac arrhythmia, and they attenuate that hypercontractility and as you can see going from an untreated OECM to a CMI treated OHCM heart. The septum may remain sick for quite some time, but the LV cavity just enlarged the speed of that hypercontractility attenuate closer to normal, the [indiscernible] obstructure is abolished, and that [indiscernible] of that mitral valve is realigned and this can significantly improve mitral regurgitation. We also know that over time, this can normalize or improve left atrial affects. PMIs directly target the ACM pathophysiology by reducing the number of force-generating cross-bridge formation closer to normal. HCM is a disease of the cardiac arrhythmia and cardiac myosin inhibitors attenuate that hypercontractility, which is the hallmark of HCM, closer to a normal magnitude of cross-bridge cycling. And in doing so, it improves the myocardial amigetics [indiscernible] obstruction and the goal is also to make our patients feel and function better. CMIs have improved OPM care, and I would argue that in my clinical practice, it has been a game changer over the last several years. But there remains significant unmet needs and the need for greater efficacy and convenience in allowing these PMIs to be more democratically available across the United States. First-generation CMI have proved the mechanism of modulating cross formation and attenuating that closer to normal, they are effective in reducing the less ventricular track gradient by 50% to 60%, they do improve feel and function and was seen this in multiple clinical trials. They increased [indiscernible] cardiopulmonary exercise testing and the improved patient reported outcomes, KCCQ and NYHA and there is an established market with a validated mechanism. However, there is an opportunity for next-generation CMI. There remains a large percentage of patients who are nonresponders or partial refounders there is an LBS cost that caps the gradient benefit and the long titration in monitoring is a significant burden for patients, health care providers and health systems in the long top life, the flow on second reversal of currently available agents may make them cumbersome to you to get to target dose, but also to be able to revert.

Thank you, Dr. Harper. Let's speak now to the obstructive HCM data presented today at AHA. The study presented today was the open-label extension of the Phase II study previously shared at ACC earlier this year. In this study, all 42 patients chose to participate in a 52-week extension where following a washout, they were rebaseline on cardiopulmonary exercise testing, or CPET, echocardiography and clinical parameters and then initiated on 40 milligrams BID of BHB 893 with the opportunity to titrate at week 1 and net to 600 milligrams BID. Patients had repeat assessment throughout the study, notably by CPET measurements that were repeated at week 52. After the washout from the core treatment period, gradients and clinical parameters were noted to revert to pretreatment levels. These patients had a high baseline gradient. Stepping back, we believe the results from this study highlight the efficacy profile of BHB-1893 across clinical activity and biomarkers and in particular, highlight how the rapidly gradient responses with more time on therapy and in a larger cohort translate to improvements in exercise capacity and symptoms. This slide shows the Valsalva gradient response in the 12-week core and at 52 weeks in the OLE. 2 major takeaways for us were that the 52-week OLE confirmed the rapidity, depth and durability of grading response with BHB-1893 in a larger 42-patient cohort, and also demonstrated a meaningful response rate prior to titration, which was notably high with 67% of patients achieving a Valsalva gradient less than 30 millimeters of mercury by week one. Overall, there is a high proportion of patients that achieved complete gradient response in the study, as defined by a Valsalva also known as provoked gradient less than 30 millimeters of mercury. What is also notable is that in addition to 2/3 of patients achieving a Valsalva complete response at titration, 83% achieved a resting gradient less than 30 at that same early time frame. NT-proBNP is a blood biomarker of heart failure. This also demonstrated a rapid, deep and durable response. Importantly, NT-proBNP is often used by physicians to roll out active heart failure, and for the high proportion of patients with normalization this parameter was particularly encouraging. Measures taken from cardiopulmonary exercise testing, or CPET, are important parameters of patients exercise capacity and function. Peak VO2 is also a key regulatory endpoint in HCM and both peak VO2 and EDC2 are significantly associated with mortality and adverse clinical outcomes in patients with HCM. We were, therefore, highly encouraged to see a 2.7 per kg per minute improvement in peak O2 and at 52 weeks from the start of the OLE. We believe this may reflect further consolidation of clinical improvement with more time on therapy and is associated with the rapidity depth and durability of gradient relief achieved on BHB-1893. A majority of patients had large changes in peak VO2 as you can see on the rent. Note that all these patients or on cycle ergometer, which historically has had a smaller delta than treadmill for CPAP testing. Likewise, the negative 4.1% VE/VCO2 slope improvement was very encouraging. The clinical improvements seen were highly consistent with both [indiscernible] and biomarkers. We noted a 17.3 point improvement in KCCQ-CSS with the mean ending in the mid-90s, 100 being the upper limit of the assessment. Furthermore, 45% of patients had large 20-plus point improvement. Our New York Heart Association class, which is a physician-measured scale of heart failure symptoms, the data were very consistent. Patients improved in the core period and after withdrawal therapy generally return to baseline. What is important is that after 52 weeks of therapy in the OLE, 60% of patients were Class I, which is consistent with these individuals having no limitation in ordinary physical activity. The data from this 1-year extension were also supportive of potential disease modification in a way that's highly consistent with the nonobstructive HCM data presented earlier this year, and to which Dr. Owens will speak to shortly. Core to the genetics and pathophysiology of HCM is a hyper contract state of cardiac myosin. It was encouraging, therefore, that we saw normalization in patients with hypercontractile ventricles to a greater extent than those with normal LVE asset baseline. As we've spoken to the investigator and scientific community about this finding, it raises a hypothesis of BHB-1893 potentially acting in a state-dependent manner, which we plan to lose state in further mechanistic work. Notably, now with over 50 patient years of data in this study, we've only had 2 patients with LVEF measured below 50%. As we look at other measures of systolic function, it's important to note the stability of less ventricular global longitudinal strain. This is another measure of heart function and can sometimes detect cardiac dysfunction before LVEF reduction. Importantly, it was stable throughout the study. What was particularly encouraging from these data is that key biomarkers of disease -- this study provided a unique opportunity to explore the potential for disease modification in OHCM after removal of therapy, given that patients were washed out after both core treatment period and OLE. Similar reductions in exposure and rebound in the app were noted between the core study and OLE. What's particularly encouraging from these data is that key biomarkers of disease, including gradient, both resting Valsalva and NT-proBNP had less rebound after the 52-week treatment period. This was statistically significant. What was also seen was further deepening improvements in Maximal LV wall thickness over time, which was highly consistent with the improvement seen in nonobstructive HCM for BHB-1893, a thick and ventricle is a core part of the definition of HCM. And so this finding, again, may suggest potential for reverse remodeling and ultimately disease modification. Overall safety continues to be encouraging with no on-treatment severe or serious AEs. Data from early provided further evidence for dose selection of BHB-1893 and further confirm the "fixed dose for most paradigm, which we plan for Line heart HCM. As you can see, the majority of patients in a similar proportion to previous are served by the starting dose with 60 milligrams providing significant additional patient coverage as well. Overall, we believe these data continue to show best-in-disease potential for BHB-1893. First, we believe we have the simplest dosing regimen. It's notable that 2/3 of patients had a complete Valsava gradient response already at 1 week prior to titration. Second, the latest clinical efficacy data provide potential evidence that rapid and deep improvements of gradient could translate to larger improvements in CO2 and KCCQ over time. Third, these data support the notion that BHB-1893 could have a disease [indiscernible] impact, consistent with the data observed in nonobstructive HCM. Finally, we were highly encouraged by the very consistent clinical profile in obstructive HCM now with a larger cohort of the chosen starting dose for Phase III studies. I'd like to pass it now to our Chief Scientific Officer, Marc Evanchik to speak to emerging preclinical data supporting the mechanism of BHB-1893.

Thank you, Dr. Murdoch. Cardiac myosin inhibitors are the first drugs in HCM to act on the cause of the disease and not just its downstream symptoms. HCM is a disease of the sarcomere, too many myosin heads engaged with [indiscernible], which makes the hypercontractile, stiff and slow to relax. 2 CMIs are now approved, mavacamten and apicamten, both improve obstruction exercise capacity of symptoms. Patients who stay on treatment also show the heart remodeling LV mass walls, the left atrium shrinks and biomarkers of wall stress and injury come down. And that's why we think the mechanism is proven. The open question isn't whether to inhibit myosin, it's how to do it better. 1893 binds to the same target, the S-1 [indiscernible] myosin and reduces excess cross-bridge formation where we differ is pharmacology. First, the effect of half life is about 12 hours, not days. Onset is rapid, and so is reversal. If a physician needs to adjust or stop the drug, the effect follows within days, not over weeks. Second, exposure response for [indiscernible]. A change in drug levels doesn't turn into a steep drop in injection fraction. That's the safety issue that drives the monitoring burden in this class today. Third, PK should be predictable across patients. Metabolism runs through several pathways and the parent drug is cleared by the kidneys. So we don't expect significant drug-drug interactions or 4 metabolizer out layers. So this is the same proven mechanism with a PK profile design for easier dosing and control. In addition to the favorable PK, we are also seeing the pharmacodynamic distinct what the drug does to the disease tissue. We tested an engineering -- engineered heart tissue made from human cells carrying the R403Q myosin mutation, a classic HCM variant alongside wild-type tissue. The model shows the -- on the left, HCM and the wild-type tissue generated about the same peak force, but the HCM tissue relaxes later. In the second panel, RT90, the time to 90% relaxation is longer in HCM versus wild type. And under stretch, which mimics higher filling load the GAAP line -- that relaxation time gets even longer. On the right, the HCM tissue does more nonproductive work for the same force. That's the HCM phenotype [indiscernible] more work impaired relaxation. Relaxation is the defect we want to fix. Start with the force curve on the top left. At 0.3 micromolar, the concentration that has the relaxation deficit peak force falls by only 10% and by the same amount in HCM and wild-type tissue. The curves sit on top of one another. On the right, relaxation time in HCM falls by about 19 milliseconds toward the wild type line. And under stretch, the stress response is reduced. Nonproductive work also comes down. The point is that we restore relaxation without giving up contraction, which is why we expect more predictable LDL changes in patients. Here is the same experiment run with all 3 molecules in the same model. For each drug, the shaded band marks the concentration that improved relaxation. Mavacamten getting the reduction benefit cost more than 75% of the normal force in the loyal type tissue with apecamten, it's about 50, with 1893 to about 10%. There's a second difference for [indiscernible], the wild type and mutant curves separate. So the drug behaves differently in healthy and diseased muscle. For 1893, the 2 curves overlap. Its effect on contractility is tight and consistent. So the summary is first-generation CNIs prove that inhibiting myosin monetized the disease. 1893 is designed to deliver that diabetic benefit at a much lower systolic cost with half like measured in [indiscernible] in the clinic that can mean simpler dosing and less monitoring. Now I'm pleased to introduce Dr. Angeli Owens, who will review the Phase II diastolic data in nonobstructed HCM.

Thank you so much, Marc. It's my pleasure to be here today. And I'll walk you through the study design first of the Phase II placebo-controlled trial in nonobstructive patients. This is over 12 weeks. This data was previously presented at the European Heart Failure meeting earlier this year. So this was a study of 84 patients who were randomized to the low dose, high dose or a placebo group, as you can see outlined in the figure, and they were treated for 12 weeks prior to washout and a safety follow-up period. There was an option for dose titration, as you can see outlined by the white arrows. These were patients just to remind you of the inclusion who had systematic nonobstructive HCM with an LVEF fitter than or equal to 60 in Class 2 or 3 NYHA. That was shown to be nonobstructive at baseline by both [indiscernible], and they had a KCCQ somewhere between 30 and 85. The primary endpoint of this Phase II study dose finding with safe, including the LVEF of less than 50% incidents, as well as secondary endpoints that were looked at for efficacy, including biomarkers, our markers with [indiscernible], which in this study were KCCQ, PC02, and also diastolic information that we will focus on today. As a reminder, there was a dose titration criteria as with many of our placebo fetal trials, this is a titration based on ejection fraction and not including clinical judgment. So what we saw in terms of biomarkers first. We have NT-proBNP on the left, and troponin on the right. And I'll just highlight though, it's an orange low dose, in red, high dose; and another orange, light orange. So what we saw was a 68% decrease from baseline in the high-dose group that fell rather quickly, so it stays on the X axis. And we saw that many patients at the high dose dropped below the threshold of normal for NT-proBNP. On the right for troponin, we saw again a 60% decrease from baseline in the high-dose group. Now let's turn our attention to diastolic function. When we see those biomarkers improve quickly after dosing. We wonder what's happening on the inside of the heart. And in terms of that, we look at diastolic function by echo when we don't have an invasive test. And so we're looking by echo to see whether or not the part is relaxing better [indiscernible] of what Marc showed you from the engineered heart tissue data. So we looked at Prime Velocity, which is a marker of relaxation at 12 weeks. And you can see here the placebo group, low dose and high dose, and we look at the steps time on the septal side of the ventricle and the lateral pride. And I'll remind you that in our patients with HCM, typically the septum is more disease. They often have less response than the septum and the lateral wall typically is less disease. And so you can see there a dose dependence on the lateral side, improvement in septal Prime again over time. And those velocities move from abnormal on the right side, which is pretty typical for the nonobstructive patients with HCM towards the normal range of 12 weeks. Now what I'll tell us about diastolic dysfunction in a heart. We look at relaxation. We also look at evidence of chronic pressure overload and that generally is reflected in the size of the left atrium over time in our patients with HCM. And what we can see here, looking at [indiscernible], which is a marker of filling pressures and then by left atrial volume index in the middle and right-sided panels is that we saw a pretty marked improvement between low dose and high dose in patients left atrial volume index. And you can see a baseline again, typical for an HCM population who symptomatic with nonobstructive HCM. The left atrial size is larger baseline. And by relieving that pressure relaxing the heart, we see an improvement toward normal in the aggregate population of the left atrium volume index. These are other markers of structure of the heart, which is important as we look at longer-term remodeling with targeted therapies. We'd like to see that the part is moving toward a more normal state, remodeling in a positive sense. And so here, I have shown for you less ventricular mass index on the left and less ventricular wall thickness on the right. And you can see dose dependence between low dose and high dose, improvements in both the overall [indiscernible] index of the heart as well as the wall thickness. And you can see that on the placebo group really no improvement or a slight worsening. And this is, again, over 12 weeks of treatment. So let's turn our attention to safety. As with any Phase II trial, we really are looking at dose response, we are looking at dose tolerance and safety. And you can see a pretty even response between the low and the high dose when you're looking at AEs. One thing we always look for by mechanism of action that the cardiac myosin inhibitors is what is going to be the incidence of LVEF less than 50%. Dr. Murdoch some time talking about this in the obstructive population [indiscernible] the non-obstructive population where we did see 4 patients, which is 7% of the cohort had a transient drop in ejection fraction to less than 50%. You can see here that the LVEF in those 4 participants was in the high 40s between 46 and 49 and all of them returned to greater than or equal to 50% following dose reduction. We had no patients in this study that were discontinued for a low EF. So in summary, I think we've shown here the mechanistic validation of CMI in disease states and we correlated that from the engineered heart tissue data that Marc showed into our human patients with non-obstructive HCM. In particular, in the nonobstructive group, where they may not have as much hyperdynamic function, it's really important to be able to accomplish this benefit in diastolic function with minimal systolic cost. And we are, of course, in the clinic, looking for the easiest, most simple way to do this for our patients in the real world where we have many patients who are looking for targeted therapies. So ideally, a simple dosing and really targeted benefit would be the idea. Dr. Murdoch, back to you.

Thank you, Dr. Owens. So we've spoken a fair bit today about the emerging clinical and preclinical profile of BHB-1893. Ultimately, we are a company laser-focused on improving the lives of patients with HCM, and we believe this profile could ultimately translate to a therapy with meaningful efficacy and safety for patients. We also believe that the profile of BHB-1893 with minimal or no titration and predictable PK could enable broader access by allowing cardiology practices, both in the community and centers of excellence to prescribe a potentially highly efficacious therapy. Importantly, the immediate onset of action of BHB-1893 at the starting dose provides an opportunity for patients and physicians to quickly achieve an effective dose. Given the minimal need for titration, we believe this has the potential to be an important enabler of utilization in the future beyond HCM specialty centers. For our Phase III study, [indiscernible] HCM, we have planned availability of a one-step titration at 4 weeks. Given the data in Phase II where titration was conducted at week 4, we believe further time on the starting dose prior to titration may minimize further need for higher doses. However, we also recognize that there exists an important opportunity to demonstrate differentiated clinical activity with BHB-1893. And we want to serve patients with residual ingredients and who may require higher doses. Therefore, we will have availability of a higher dose, 60 milligrams BID in that study. Our market research has pointed to the relatively slow uptake of the existing medications in the community relating to the challenges and burden associated with the current multistep titration paradigm. We are there for now planning an additional Phase IIb study to evaluate a 40-milligram BID fixed dose, which we believe could be a complementary dosing regimen for new patient starts, for easier to treat patients and community practices. We see a potential future where community practices feel comfortable prescribing a fixed dose, and those patients who require further dose modification could be referred to a center of excellence if needed. This is similar to specialists and subspecialists collaboration for other complex chronic disease management and could help expand access while ensuring patients receive the most efficacious dose of BHB-1893. We are well underway into planning Trueheart-HCM and where we will study a fixed 40-milligram dose and no titration visits over the course of the study. This study would also enable us to generate further data in symptomatic HCM and on top of standard of care in a global population. We recently received supportive feedback from FDA on the fixed-dose approach and are working to finalize the protocol for initiation in the first half of 2027. We look forward to providing further updates as we move to initiating the study. Stepping back, we are pursuing a highly comprehensive development plan for BHB-1893 in both forms of HCM. Our partner Hengrui continues to execute on a Phase III study on top of standard of care which is fully enrolled and for which we are expecting top line results in the first half of next year. We plan to use this study as part of our filing package as we've previously articulated. We have initiated Lionheart HCM which is a global Phase III study head-to-head with metoprolol and with an option for a single titration at week 4. We believe this will generate important data to support an earlier role of BHB-1893 in the care of HCI. We're planning Trueheart, which we believe could enable a complementary fixed dose approach as well as generating further global data on top expander repair. Finally, we're initiating Nobleheart HCM, which is our global nonobstructive HCM Phase III study. Here, we seek to confirm the compelling clinical activity demonstrating Phase II including some of the data shared today by Dr. Owens in a global Phase III program. All patients from global studies will have the opportunity to enroll in heart song LTE for long-term access to BHB-1893 and follow-up to understand the impact of BHB-1893 with more chronic administration. Finally, we wanted to provide a brief overview of what's to come. Next year, we look forward to sharing multiple data readouts, including the full Phase III data set from the HRS 301 study, long-term data from an open-label extension of the non-obstructive Phase II study and a planned interim analysis from our Phase III OHCM Lionheart HCM study that will be a key component of our potential first NDA filing. We are well capitalized to execute on our comprehensive development program with cash runway into 2029. We sincerely appreciate everyone who is able to join us today. Now we'd like to open up the call for questions. Operator, proceed to share instructions, please, and open the call for a Q&A session.

[Operator Instructions] One moment for questions. Our first question comes from Andrew Tsai with Jefferies.

Thanks for these great set of updates. My first question is that it's just -- it's pretty apparent that this 52-week data you're sharing obstructive, longer dosing does get you better efficacy over time. But to me, it also supports the rationale of using LVOT as a predictive marker for this interim analysis that you're having for the Lionheart study that reads out in the second half 2027. So for that interim, can you tell us how you've powered that interim at week 12, what are you assuming for drug response? What are you assuming for placebo response? And then I have a follow-up.

Thanks, Andrew. I appreciate the question. Nice to hear from you. So we have articulated publicly that the Lionheart HCM study has an interim analysis, that interim analysis will be a 12-week endpoint. As you know, it will include gradient data, 40 patients on drug, 20 patients on placebo. We believe we're well powered given the data that we saw in both the core study and the long-term extension study there. I think you raised an important point, which is that there is previous data as well, suggesting a relationship between improvements, ingredients and feel and function. And certainly, part of the reason why the initial work was done to ultimately enable peak VO2 as an endpoint in this disease was that relieving obstruction can it help improve cardiac output and ultimately exercise capacity. And so we were very encouraged to your point by the data today, continuing to demonstrate that consolidating over time.

Right. And secondly, for your compound, there seems to be minimal LVEF cost. And I think interestingly, your positioning for 1893 is still some use of echos, not necessarily 0 use of echo. So can you talk about your overall strategy of ultimately securing a more relaxed echo monitoring schedule for your eventual label for both obstructive and non-obstructive? How do you peel back the REMS requirement to the point there actually might not be rents?

Yes. As you point out, this is a potential targeted therapy, and we believe that there's a very good set of treatment targets for patients that are objective and echo based. And so as you articulate, we think that echos are part of general cardiologist practice. In fact, our productive part of the treatment paradigm. Certainly, one of the challenges has been that the number of echoes required to get patients on to effective dose is quite high. And so we have a 2-part strategy to really help relieve that. One is what we've heard through all of our market research is that the community physicians struggle more with the Valsalva echos and feeling confident in making dosing decisions based on those. And so that's where we think this 40-milligram starting dose where potentially patients could be on a longer period of time in the community. That's less of an issue at centers of excellence. At the COEs, what we've heard is really that the burden of doing these -- the high number of echoes to get patients on to therapy in particular has limited patient starts. And that's where really limiting the number of titration steps we think is going to be important and the clinical profile of 1893 enables that. The second piece, which we did not speak to today at length, but which we will in the coming months, is that we continue to work with regulators on how to further relieve a need for highly regimented echos. And so moving away from highly regimented echos to echos that may be more physician-directed and physician and symptom guided, we think, are going to be an important part of the future, which really is just clinical practices, right? It's a physician is able to make a decision. So we'll look forward to sharing more about that strategy into next year as we continue to engage with.

Our next question comes from Tyler Van Buren with TD Cowen.

I have a couple for you. The first one is just I want to follow-up on the increased peak VO2 improvement up to 52 weeks because it's 1 of the more interesting incremental observations with the additional follow-up from the OLE here. So -- can you just elaborate on the consolidation of treatment benefit that's being observed and why this could make sense and being mechanistically differentiated from the first-gen CMIs. And then the second one is on the new Trueheart trial design, it's great, obviously. So can you elaborate on what led to its announcement. Was it discussions with physicians or the FDA? And then also, when could we get the data? And how could it impact an eventual label?

Thanks, Tyler, nice to hear from you. So maybe the first question, I think our belief, and this is -- this is work that we continue to learn more about as we get more echocardiographic data in these patients and understand the relationship between those echo parameters in pVO2 is that the deep improvements in gradient paired potentially with diastolic benefit, it could be why we're continuing to see consolidation. Maybe I'll pass it to Dr. Owens as well to speak a bit of her perspective on the data.

Yes, I would agree with that. I think that the deeper the gradient reduction, the better your NT-proBNP gets, we've seen that, that correlates with the magnitude of improvement of cardiac output and ultimately, peak VO2. The other thing that I would add to that is that we know many of our patients with symptomatic obstructive HCM are relatively deconditioned, because of years of being limited from a cardiac standpoint. And so the other thing that we may be seeing is that as the gradient is relieved and they start to feel better and they're doing more, that they become reconditioned and that may also ultimately affect peak VO2 at week 52. This is a particularly unique study because despite all of our CMI trials, we really don't have this data of peak VO2 at week 52 on drug in a trial. And so I think it's very important that it was investigated and a pretty dramatic improvement.