Welcome to the Braveheart Bio call today. My name is Josh, and I will be your operator for today's call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session. 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 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 Perelman School of Medicine at the University of Pennsylvania. Dr. Owens is also Medical Director of Penn Center for Inherited Cardiovascular Disease.
Also joining us is Dr. Mariko 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, while 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 four.
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 in 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 non-obstructive HCM, we are in the midst of initiating NOBLEHEART, 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 non-obstructive 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 one-year follow-up in obstructive HCM, in addition to the nHCM data shared prior this year. We believe that in totality, the pharmacologic and clinical profile of BHB-1893 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. Mariko Harper, who will provide an overview of HCM and the current treatment landscape. Dr. Harper.
Thank you, Dr. Murdoch. 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 LVH that explains the full magnitude, although concurrent conditions such as hypertension and aortic stenosis are common. HCM is classified into obstructive and non-obstructive HCM based on the presence or absence of left ventricular outflow tract obstruction.
As you can see, on the left is your healthy heart, and the big difference between the oHCM and the nHCM is the presence of a left ventricular outflow tract obstruction that can be at rest or dynamic, and the magnitude is greater than or equal to 30 millimeters of mercury. But regardless of obstruction, there is a commonality of thickening, a small LV chamber, a hyperdynamic ejection fraction. HCM is a serious and lifelong progressive cardiovascular disease, with the underlying disease burden made up of diastolic dysfunction with impaired myocardial relaxation, elevated LV stiffness, and frequently increased LV filling pressures. There can be ongoing cardiac damage due to chronic myocardial stress, and this often results in an elevated biomarker 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, but can cause significant patient limitations, including shortness of breath, chest tightness or chest pain, and fatigue, all of which are worse with exertion. There can be the presence of near-syncope and syncope, both with activity or sometimes even at rest due to arrhythmic potential. The risks with hypertrophic cardiomyopathy over a lifetime include an increased burden of atrial fibrillation, the development of symptomatic heart failure, including a small subset of patients that go on to end-stage disease requiring heart transplantation, the presence of stroke, especially when there is atrial fibrillation, as well as a small subset of patients that suffer sudden cardiac death. In the U.S., we are looking at almost 1 million patients 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 one in 200 to one in 500 patients. Once a patient develops obstructive hypertrophic cardiomyopathy, there is a significant burden on health systems and patients' quality of life, with over one in three being hospitalized annually for all cause, and that oHCM 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, and these include beta blockers, non-dihydropyridine calcium channel blockers, and these are really targeting the symptoms, but there is limited HCM trial evidence for effect and long-term benefit and disease modification.
Septal reduction therapy is also recommended in a subset of patients who have severe limiting symptoms and severe gradients who have failed first-line therapy, but they require an experienced 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 sarcomere, and they attenuate that hypercontractility. As you can see, going from an untreated oHCM to a CMI-treated oHCM heart, the septum may remain thick for quite some time, but the LV cavity starts to enlarge, the sleeve of that hypercontractility attenuates closer to normal, the outflow tract obstruction is abolished, and that systolic anterior motion 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 size. CMIs directly target the HCM pathophysiology by reducing the number of force-generating cross-bridge formation closer to normal. HCM is a disease of the cardiac sarcomere, and cardiac myosin inhibitors attenuate that hypercontractility, which is the hallmark of HCM, closer to a normal magnitude of cross-bridge cycling. In doing so, it improves the myocardial energetics, the diastolic function, relieves the left ventricular outflow tract obstruction, and the goal is also to make our patients feel and function better. CMIs have improved oHCM 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 a need for greater efficacy and convenience in allowing these CMIs to be more democratically available across the United States.
First-generation CMIs have proved the mechanism of modulating cross-bridge formation and attenuating that closer to normal. They're effective in reducing the left ventricular outflow tract gradient by 50%-60%. They do improve feel and function, and we've seen this in multiple clinical trials. They increase peak VO2 on cardiopulmonary exercise testing, and they improve patient-reported outcomes, KCCQ and NYHA. There's an established market with a validated mechanism. However, there is an opportunity for next-generation CMIs. There remains a large percentage of patients who are non-responders or partial responders. There is an LVEF cost that caps the gradient benefit, and the long titration and monitoring is a significant burden for patients, healthcare providers, and health systems. The long half-life, the slow onset and reversal of currently available agents may make them cumbersome to use, to get to target dose, but also to be able to reverse.
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 re-baselined on cardiopulmonary exercise testing, or CPET, echocardiography, and clinical parameters, and then initiated on 40 mg BID of BHB-1893, with the opportunity to titrate at week one and week two to 60 and 80 mg. Patients had repeat assessments 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 pre-treatment 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 rapid and deep 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. Two major takeaways for us were that the 52-week OLE confirmed the rapidity, depth, and durability of gradient 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 was 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 prior to the one-week titration, 83% achieved a resting gradient less than 30 at that same early time point. NT-proBNP is a blood biomarker of heart failure. This also demonstrated a rapid, deep, and durable response. Importantly, normal NT-proBNP is often used by physicians to rule out active heart failure, and so the high proportion of patients with normalization of this parameter was particularly encouraging. Measures taken from cardiopulmonary exercise testing, or CPET, are important parameters of patients' exercise capacity and function.
Peak pVO2 is also a key regulatory endpoint in HCM, and both peak pVO2 and VE/VCO2 are significantly associated with mortality and adverse clinical outcomes in patients with HCM. We were therefore highly encouraged to see a 2.7 mils per kg per minute improvement in peak pVO2 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 pVO2, as you can see on the right. Note that all these patients were on cycle ergometer, which historically has had a smaller delta than treadmill for CPET testing. Likewise, the - 4.1 VE/VCO2 slope improvement was very encouraging. The clinical improvements seen were highly consistent with both CPET 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+ point improvement. On 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 of therapy, generally returned 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 one-year extension were also supportive of potential disease modification in a way that is highly consistent with the non-obstructive HCM data presented earlier this year, and to which Dr. Owens will speak to shortly. Core to the genetics and pathophysiology of HCM is the hypercontractile state of cardiac myocytes.
It was encouraging, therefore, that we saw normalization in patients with hypercontractile ventricles to a greater extent than those with normal LVEF at baseline. As we have 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 elucidate in further mechanistic work. Notably, now with over 50 patient years of data in this study, we have only had two patients with LVEFs measured below 50%. As we look at other measures of systolic function, it is important to note the stability of left 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 EF were noted between the core study and OLE. What is particularly encouraging from these data is that key biomarkers of disease, including gradient, both resting and 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 improvements seen in non-obstructive HCM for BHB-1893. A thickened 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 continued to be encouraging with no on-treatment severe or serious AEs.
Data from the OLE provided further evidence for dose selection of BHB-1893 and further confirmed the, quote, "fixed dose for most" paradigm, which we plan for LIONHEART-HCM. As you can see, the majority of patients, in a similar proportion to previous, are served by the starting dose, with 60 mg 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 Valsalva gradient response already at one 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 pVO2 and KCCQ over time. Third, these data support the notion that BHB-1893 could have a disease-modifying impact consistent with the data observed in non-obstructive HCM.
Finally, we were highly encouraged by the very consistent clinical profile in obstructive HCM, now with a larger cohort at 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 engage with actin, which makes the heart hypercontractile, stiff, and slow to relax. Two CMIs are now approved, mavacamten and aficamten. Both improve obstruction, exercise capacity, and symptoms. Patients who stay on treatment also show the heart remodeling back. LV mass falls, the left atrium shrinks, and biomarkers of wall stress and injury come down. It'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 S1 motor head of myosin, and reduces excess cross-bridge formation. Where we differ is pharmacology. First, the effective 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 LVEF is shallow. A change in drug levels doesn't turn into a steep drop in ejection 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 poor metabolizer outliers. This is the same proven mechanism with a PK profile designed for easier dosing and control. In addition to the favorable PK, we are also seeing the pharmacodynamics distinct, what the drug does to the disease tissue.
We tested it in engineered heart tissue made from human cells carrying the R403Q myosin mutation, a classic HCM variant, alongside wild-type tissue. The model shows the disease. On the left, HCM and the wild-type tissue generate 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. Under stretch, which mimics higher filling load, the gap widens. The relaxation time gets even longer. On the right, the HCM tissue does more non-productive work for the same force. That's the HCM phenotype in a dish, 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 halves 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. Under stretch, the stress response is reduced. Non-productive work also comes down. The point is that we restore relaxation without giving up contraction, which is why we expect more predictable LVEF changes in patients. Here's the same experiment run with all three molecules in the same model. For each drug, the shaded band marks the concentration that improves relaxation. Mavacamten, getting the reduction benefit costs more than 75% of the normal force in the wild-type tissue. With aficamten, it's about 50. With 1893, it's about 10%. There's a second difference. For mavacamten and aficamten, the wild-type and mutant curves separate, so the drug behaves differently in healthy and diseased muscle. For 1893, the two curves overlap. Its effect on contractility is tight and consistent.
The summary is, first-generation CMIs prove that inhibiting myosin modifies the disease. 1893 is designed to deliver that diastolic benefit at a much lower systolic cost, with half-life measured in hours. In the clinic, that can mean simpler dosing and less monitoring. Now I'm pleased to introduce Dr. Anjali Owens, who will review the phase II diastolic data in non-obstructed HCM.
Thank you so much, Marc. It's my pleasure to be here today. I'll walk you through the study design first of the phase II placebo-controlled trial in non-obstructed patients. This is over 12 weeks. This data was previously presented at the European Heart Failure Meeting earlier this year. 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. 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 inclusion, who had symptomatic non-obstructive HCM with an LVEF greater than or equal to 60 at baseline, class II or III NYHA.
They were shown to be non-obstructed at baseline by both resting and Valsalva gradients, and they had a KCCQ somewhere between 30 and 85. The primary endpoint of this phase II study, dose finding, was safety, including the LVEF of less than 50% incidence, as well as secondary endpoints that were looked at for efficacy, including biomarkers or markers of filling function, which in this study were KCCQ, peak VO2, 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-controlled trials, this is titration based on ejection fraction and not including clinical judgment. What we saw in terms of biomarkers first. We have NT-proBNP on the left and troponin on the right.
I'll just highlight for you the placebo is in orange, low dose in red, high dose in another orange, a light orange. What we saw was a 68% decrease from baseline in the high-dose group that fell rather quickly, so days on the x-axis. 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. 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. In terms of that, we look at diastolic function by echo when we don't have an invasive test. We're looking by echo to see whether or not the heart is relaxing better.
These are corollaries of what Marc showed you from the engineered heart tissue data. We looked at E prime velocity, which is a marker of relaxation at 12 weeks. You can see here the placebo group, low dose, and high dose. We look at the septal E primes on the septal side of the ventricle and the lateral E prime. I'll remind you that in our patients with HCM, typically the septum is more diseased. We often have less response in the septum, and the lateral wall typically is less diseased. You can see there a dose dependence on the lateral side, improvement in septal E prime, again, over time. Those velocities move from abnormal on the right side, which is pretty typical for the non-obstructed patient with HCM, towards the normal range at 12 weeks.
What else tells 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. What we can see here, looking at E over E prime, which is a marker of filling pressures, and then by left atrial volume index in the middle and the right-sided panels, is that we saw a pretty marked improvement between low dose and high dose in patients' left atrial volume index. You can see at baseline, again, typical for an HCM population who's symptomatic with non-obstructive HCM, their left atrial size is large at baseline. By relieving that pressure, relaxing the heart, we see an improvement toward normal in the aggregate population with left atrial 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 would like to see that the heart is moving toward a more normal state, remodeling in a positive sense. Here, I have shown for you left ventricular mass index on the left and left ventricular wall thickness on the right. You can see dose dependence between low dose and high dose improvements in both the overall mass index of the heart as well as the wall thickness. You can see that on the placebo group, really no improvement or slight worsening. This is, again, over 12 weeks of treatment. 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.
You can see a pretty even response between the low and the high dose when you are looking at AEs. One thing we always look for by mechanism of action with the cardiac myosin inhibitors is what is going to be the incidence of LVEF less than 50%. Dr. Murdoch spent some time talking about this in the obstructive population. Here is what we know in the non-obstructive population, where we did see four 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 four 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.
In summary, I think we have shown here that there can be mechanistic validation of CMIs 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 non-obstructive group, where they may not have as much hyperdynamic function, it is really important to be able to accomplish this benefit on diastolic function with minimal systolic cost. 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. Ideally, simple dosing and really targeted benefit would be ideal. Dr. Murdoch, back to you.
Thank you, Dr. Owens. We have 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 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, LIONHEART-HCM, we have planned availability of a one-step titration at four weeks. Given the data in phase II, where titration was conducted at week four, 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 gradient and who may require higher doses. Therefore, we will have availability of a higher dose, 60 mg 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 multi-step titration paradigms.
We are therefore now planning an additional phase IIb study to evaluate a 40 mg 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 specialist and subspecialist 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, where we will study a fixed 40 mg dose and no titration visits over the course of the study. This study would also enable us to generate further data in symptomatic oHCM 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 this 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 four.
We believe this will generate important data to support an earlier role of BHB-1893 in the care of oHCM. We're planning TRUEHEART-HCM, which we believe could enable a complementary fixed-dose approach, as well as generating further global data on top of standard of care. Finally, we're initiating NOBLEHEART-HCM, which is our global non-obstructive HCM phase III study. Here, we seek to confirm the compelling clinical activity demonstrated in 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 HEARTSONG 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 dataset from the HRS-1893-301 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 was able to join us today. Now, we would like to open up the call for questions. Operator, proceed to share instructions, please, and open the call for a Q&A session.
Thank you. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. One moment for questions. Our first question comes from Andrew Tsai with Jefferies. You may proceed.
Hi. Good afternoon. Thanks for these great set of updates. My first question is that it is pretty apparent that this 52-week data you are sharing in 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 are having for the LIONHEART-HCM study that reads out in second half 2027. For that interim, can you tell us how you have powered that interim at week 12? What are you assuming for drug response? What are you assuming for placebo response? Then I have a follow-up. Thank you.
Thanks, Andrew. I appreciate the question. Nice to hear from you. 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 are well-powered given the data that we saw in both the core study and the long-term extension study there. I think you raise an important point, which is that there is previous data as well suggesting a relationship between improvements in gradient and fill and function. 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 help improve cardiac output and ultimately exercise capacity.
We were very encouraged, to your point, by the data today continuing to demonstrate that consolidating over time.
Great. Thank you. Secondly, for your compound, there seems to be minimal LVEF cost. I think interestingly, your positioning for BHB-1893 is still some use of echoes, not necessarily zero use of echoes. 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 REMS? Thank you.
Thank you. Yes. As you point out, this is a potential targeted therapy, and we believe that there is a very good set of treatment targets for patients that are objective and echo-based. As you articulate, we think that echoes are part of general cardiologist practice. In fact, a productive part of the treatment paradigm. Certainly, one of the challenges has been that the number of echoes required to get patients onto effective dose is quite high. We have a two-part strategy to really help relieve that. One is, what we have heard through all of our market research is that the community physicians struggle more with the Valsalva echoes and feeling confident in making dosing decisions based on those.
That is where we think this 40 mg starting dose, where potentially patients could be on a longer period of time in the community, that is less of an issue at centers of excellence. At the COEs, what we have heard is really that the burden of doing these, the high number of echoes to get patients onto therapy in particular has limited patient starts. That is where really limiting the number of titration steps we think is going to be important, and the clinical profile of BHB-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 echoes.
And so, moving away from highly regimented echoes to echoes 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 practice, right? It's where 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 regulators.
Very good. Thank you.
Thank you. Our next question comes from Tyler Van Buren with TD Cowen. You may proceed.
Hey, guys. Thanks very much for the webinar. I have a couple for you. The first one is just I wanted to follow up on the increased peak VO2 improvement up to 52 weeks, because it's one 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 be mechanistically differentiated from the first-gen CMIs? And then the second one is on the new TRUEHEART-HCM 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. Maybe the first question, I think our belief, and 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 and peak VO2, is that the deep improvements in gradient paired potentially with diastolic benefit 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.
Yeah, 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. 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.
I think it's very important that it was investigated and a pretty dramatic improvement.
To answer, Tyler, your second question, we've been thinking about this for a fair amount of time in terms of the 40 mg dose and the quick, rapid, and deep pharmacodynamic activity we've seen. I think for us, again, it's a matter of balancing efficacy, safety, and ease of use. I think that the combination of TRUEHEART-HCM, where we have availability of an uptitration, or sorry, of LIONHEART-HCM, where we have availability of an uptitration, now TRUEHEART-HCM, is really meant to serve the entire spectrum of patients. I would say that these data presented today, as we saw the very rapid gradient response ahead of titration and the high response rate, is really one of the things that gave us a ton of conviction about this approach as well.
Great. Thanks so much.
Thank you. Our next question comes from James Condulis with Stifel. You may proceed.
Hey, thanks for taking my question and congrats on all the progress. Maybe one on the TRUEHEART-HCM study. Just curious if the efficacy bar here is lower, just given sort of the improved flexibility it offers? Then, are these data that maybe be able to add it to the filing package next year based on your interim and the Hengrui data? Just like if there's a cut of data that could kind of supplement it. Then maybe one just for the docs. There's just so much going on in the HCM space, and would love to hear your perspectives kind of on how BHB-1893 fits into the evolving landscape here, and how compelling sort of this simplified titration is versus what others are doing in the space. Thanks so much.
Yeah. James, you raise an important point in that we are, with any therapy, we're balancing efficacy, safety, and ease of use. So, I think to your point, TRUEHEART-HCM, it really is aimed at understanding that efficacy with a fixed dose over time. I think one of the data points we don't have, which this study seeks to understand, is whether or not you get further consolidation of response at that 40 mg dose over time. We're certainly seeing from some of the remodeling data that with longer time on therapy, you seem to get further cardiac benefit. So again, those data were really in totality what led us to want to run this study. We do believe that there will be patients who require more drug and that benefit from that in terms of the gradient response.
Maybe on your second question, I can pass it over to Dr. Harper to speak a bit further.
Yeah, absolutely. I think in the era of FDA-approved cardiac myosin inhibitors, we are uncovering more and more patients who have been living with their disease for a long time. The first thing is there are not enough specialized centers to take care of all these patients, and there are more and more prescriptions for CMIs being written as physicians in the community are more and more comfortable with this, and patients are recognizing that this is a potential therapeutic option. But the easier it is to titrate and monitor these patients, the more we can keep them in their community, because patients do not want to travel hours to see a doc, and rural practices have long wait lists and echo labs that are full.
You are going to get more prescribers wanting to treat patients, wanting to feel more comfortable treating patients, and more patients who have long-established relationships with these community cardiologists willing to try therapy. You also have a drug that kicks in in a day or two. If you start feeling quickly better, that retention, that patient's faith in continuing therapy is huge. You are building a relationship with a patient where they are now willing to come back. They are willing to even travel for that subset of patients that might need that higher dose, if that is where they end up. But we can build a hub-and-spoke model with community cardiologists and centers of excellence where patients are coming in to start a therapy, almost like a beta blocker now. You can start one, see how you do, but with much more impactful magnitude of benefit and much quicker onset.
Thanks. Thanks.
Thank you. Our next question comes from Olivia Brayer with Cantor. You may proceed.
Hi. Congrats on the data, and thank you for the questions. On the washout data, I know you touched on this earlier, Travis, just being potential early evidence of reverse remodeling. Is there anything that suggests that this could be happening maybe more with BHB-1893 versus other CMIs? I know you didn't look at MRI data in this study, but what would you expect to see on MRI if this really is a reverse remodeling signal? I've got a quick follow-up on peak VO2.
Sure. Thanks, Olivia, for the question. You raise an important point. We plan to pursue cardiac MR in both obstructive and non-obstructive global studies. I would say, we'll leave it to you to do the cross-trial comparisons, but I think we feel quite confident in the data in terms of the magnitude of improvements being seen being quite significant. Everything that we've learned about BHB-1893 suggests to us that these drugs are not all built the same. That's where I think, these are all allosteric inhibitors, as you know, that can have quite pleiotropic effects in different parts of the cardiac cycle, and may have more pleiotropic effects on remodeling over time. Do you mind repeating the second question?
Yeah. It was just around MRI data. I know you didn't run or use MRI scans in this study, but just thoughts on what you would expect to see on an MRI if you had MRIs in this study, just to kind of confirm the reverse remodeling signal.
Yeah. Of course. Yeah, of course. I'll pass it to Dr. Owens to speak to that.
Sure. We do have MRI data with other CMIs, which typically show regression of hypertrophy in the way of maximal wall thickness as well as left ventricular mass index, with short-ish, meaning six months versus longer-term use out years. And we have some of that data. We don't have MRI data here, but what we do have is maximal wall thickness. And particularly in the obstructive group, we know that just relieving the gradient and that high afterload results in some degree of lessening of maximal wall thickness, and that's reflected in the 12 weeks coming down and then going back up during washout. Now, after 52 weeks, it's a much more interesting story, because then do you have some period of time, which we don't really know, where your wall thickness stays down, and in some patients
perhaps doesn't go back up. Now, we don't have real-world studies on that because most of our CMI patients remain on their CMI. But in the situations where the dose is stopped or lessened, there are patients where we've seen that it doesn't quite go back up to normal. And again, this is an area of active study. Could there be a situation where you need an initial dose to get hemodynamic benefit, and then you need more of a maintenance dose? These are all questions that are unanswered in the field, but will be increasingly important as we study these drugs. And I would just echo the statement that we're drugging the sarcomere multiple different ways, and although some of these drugs are similar, they are not the same, and we have to become more sophisticated about understanding which drug is for the right patient.
Ultimately, I think remodeling data will be very important in the non-obstructive group, where you don't have the gradient, you don't have the afterload. It's a much more pure examination of remodeling effect by the drug itself.
Okay. Yep, helpful. Agree. Are you able to disclose whether you saw much variability in peak VO2 responses and whether there were maybe particular patient characteristics associated with larger improvements there?
That's a great question, Olivia, we'll look forward to sharing more in future congresses in terms of the peak VO2 data.
Okay, great. Thank you, everybody.
Thank you.
I-
Thank you. I would now like to turn the call back over to Dr. Travis Murdoch for any closing remarks.
Well, I'd like to thank our presenters again, as well as Dr. Wu from Fuwai Hospital, who presented today the phase II data. These outside perspectives bring important context to the data we shared today. We're tremendously grateful to the patients and investigators who participated in these studies, and to the broader HCM community for their partnership in advancing the science here. We entered this year with high conviction in the clinical profile of BHB-1893, and today's presentation continues to add to that body of evidence. The opportunity to improve care for patients with hypertrophic cardiomyopathy in both obstructive and non-obstructive disease is significant. We're fortunate to be well-positioned to lead the next chapter. We appreciate the broad and sustained interest in Braveheart Bio and look forward to sharing further updates in the months ahead. Thank you.
Thank you. This concludes the conference. Thank you for your participation. You may now disconnect.