Great. Welcome everyone to the next session here. Excited to be joined by the Braveheart team. I have Travis Murdoch, CEO, and Paul Rickey, CFO. Obviously, a lot going on in the HCM space and with you guys specifically, but maybe we can just start. Travis, I think everyone knows the story pretty well, but maybe just a brief overview of the company, some of the data you've generated to date, and maybe just your perspectives on what got you excited about joining Braveheart. Great. Yeah. Thank you for having us today, James, at the conference as well. Braveheart is a late-stage clinical company focused on serving patients with hypertrophic cardiomyopathy and related conditions. We are in a really unique position right now in that we're a relatively new company, so we got started last year, and I can speak a bit to what got me very convicted on this program. But we're now going from company creation to now having roughly $500 million on the balance sheet, driving the program into multiple phase III programs in both obstructive and non-obstructive hypertrophic cardiomyopathy. Also benefiting from a fantastic partner in Hengrui who originated this program, who continues to execute very strongly on the program in obstructive HCM in their ongoing phase III study in China, as well as a phase II study that's ongoing in HFpEF. I think for me, the initial data that really got me convicted was really the gradient data that we saw in the phase I-B, which demonstrated very deep and rapid reduction in gradient, which is a key biomarker in obstructive hypertrophic cardiomyopathy, which was then replicated in the phase II study as well, and which we'll be sharing more data in a one-year open label extension of that phase II study at AHA as a late breaker this year. Nice. Yeah. Makes total sense. I think taking a step back, I think obviously there's so much investor focus on HCM and an appreciation for it being a really big market. I think, naturally the other view here is that mavacamten, and really more so aficamten are generally viewed as good drugs. I guess in that context, maybe just to level set, it'd be great to hear your perspectives on where you think unmet need exists today, and how you think about the different avenues for you guys to differentiate versus what we've seen with the earlier drugs. Yeah, thanks. That's a great question. I would put a pin in non-obstructive disease, where certainly I think we can all agree there remains a very high amount of unmet need. Suddenly we had a positive study f or ACACIA-HCM, which we hope will be great for patients, we think that there's much room there to really drive better outcomes for patients. In obstructive disease, I think this is a classic market that had really no available therapies. Patients were suffering. Ultimately, surgical management and a heart transplant was really what was the end result for patients. We've moved now towards agents that certainly are efficacious, but have a number of liabilities that we think BHB-1893 could address. The first really relates to efficacy, where while the existing agents are efficacious, we think that there could be opportunities to drive efficacy even further. What we saw in the phase II study is rapid and deep reductions in gradient that look in excess of what has been seen historically in other studies. The second is that while existing agents certainly are efficacious, the liability of EF reductions has been something that has resulted in the need for multi-step titrations and multiple echoes for patients, as you know, to get them onto effective therapy. One of the key imperatives that we're driving as we move into phase III is to further simplify the initiation of these therapies and the monitoring of patients on these therapies. We think that the particularly shallow dose response curve that we've seen as it pertains to reductions in EF, in addition to a very short half-life and well-behaved pharmacokinetic properties, could result in an agent that could have very competitive efficacy, but then also a safety and monitoring regimen that could be highly differentiated. Yeah. I think one of the most interesting things from your data, like you mentioned, the sort of the rapidity of onset in terms of the gradient reduction and the depth, and sort of how that allows potentially for this very simple kind of fixed dose for most titration scheme that you guys are thinking about. Maybe just like, you mentioned some of the PK and the half-life, but all the companies in the HCM space argue they have slightly different mechanisms, and there's nuances here. Maybe help us just kind of understand, at a mechanistic level or what you've learned about this molecule, about why that's driving what seemingly is potentially a wider therapeutic index versus what we've seen with some of the other drugs. Sure. So when we got started, we had conviction that there was likely mechanistic differentiation that went beyond the differentiated pharmacokinetic properties of this molecule. Certainly the clinical data we think supports that. This was a molecule that was really designed around a shorter half-life and more balanced metabolism, which we think ultimately is going to be important for patients as it pertains to differentiation from the first-generation agents. However, as we've moved forward and we're fortunate to have a scientific team that's been working in the HCM space since the start, I would say, what we've learned is that the mechanism here does appear to be quite differentiated. I'd refer you to the recent S1, but what we demonstrated there was that in engineered heart tissue, that there is a difference in potency with other agents depending on whether or not you have a mutation in myosin. In this case, it's the R403Q mutant, which is an activating mutation that really leaves myosin in a hyperactive state. We see no differences in potency for BHB-1893, which we think is one of the reasons why the therapeutic window here has been wider. The second is that in the non-obstructive data set, the phase II data set, we saw fairly large changes and improvements in measures of diastolic function, in particular septal and lateral e'. In terms of left atrial volume index, which we saw normalization, and that's never been demonstrated before, as well as early evidence already at 12 weeks of improvements in wall thickness and left ventricular mass index on echo. Those data suggested to us that we may have an agent that seems more biased towards lusitropic or diastolic effects. What we've seen now, as we have done large animal models, is that for minimal decrement in ejection fraction, roughly 3% per 1,000 ng/m L of exposure, we get over 18% increase in left ventricular and diastolic volume, which really is further evidence that this is an agent that has really outsized improvements in diastole. We are also seeing other effects that we think are notable in terms of slowing early contraction and improving isovolumetric relaxation time. That, again, suggests that not all CMIs are built the same and that this is an agent that could have particularly strong effects on those parameters, which ultimately we think could lead to greater clinical impact. Yeah. Makes sense. Yeah. It is really interesting. Maybe just to double-click into a couple of the key pieces of your phase III design in terms of dosing, again, your phase III obstructive design. In terms of dosing, again, this sort of potential for a very simple one-step titration, maybe just sort of expand upon the data in phase II that gives you confidence that you can still optimize for efficacy or get sufficient efficacy with that sort of simple scheme versus what we have seen in other contexts which are maybe a little bit more multistep. Sure. In the phase II study, there were three different cohorts. Cohort two, which starts at 40 mg, titrates to 60 mg at one week and to 80 mg at two weeks. Those data really support, if you look at gradient relief, that within a week, even before titration, most patients have gradient relief, complete gradient relief as defined by a Valsalva gradient less than 30 mg, which is the treatment target for the. What is notable there is that the titration in that phase II is quite rapid. It is at one week. It is more rapid than the other agents. It is enabled by the short half-life, so you reach steady state quite quickly. What we have observed in our studies and in other studies is that response tends to consolidate even further over time. What we are planning in our phase III, stepping back, in the phase II study, roughly 60% of patients are served by the starting dose of 40 mg. That means that this could be, even if you believe that we had a similar percent patients who require uptitration, it is fixed dose for most, which is highly differentiated from the perspective of echo burden and of obviously patient convenience. Most of these, the large majority of echo is happening in the initiation phase. However, we have chosen to wait until one month to titrate patients in the LIONHEART-HCM study, and we think that this could offer even further consolidation on the 40-mg dose, so we will be excited to share those data as they emerge. Mm-hmm. Yeah. No, I think that's really interesting. The other probably most interesting aspect is in the Part B of this obstructive study, and we can get into some of the regulatory potential paths here. You are employing blinded echoes for safety monitoring, which I think is a really interesting way to generate some data in terms of maybe disproving the negative as it relates to ejection fraction. Maybe talk about that dynamic a little bit more in terms of the purpose or the goal of implementing that in the second half of your study. Then more broadly, how you see the REMS for these class of drugs just evolving over time. Sure. I would say that there's more to come on Part B. The interactions we've had with the agency have been very positive around the notion of trying to generate prospective data that could support a less burdensome echo schedule. The start of that is really what we just spoke about, which is that if you really peel back the number of titrations required, that substantially relieves the echo burden. Independent of whether we move to Part B, we'll have that availability. What we've discussed with the agency is that we will come back to them with data, and we're fortunate to have data being generated by our partner, Hengrui, early next year, that could support the notion of moving towards more of a blinded echo paradigm in Part B, which basically means that we generate the data that could suggest that you're able to predict if a patient needs an echo based on symptoms, which is really just clinical practice, right? It's really how, in many cases with heart failure, how physicians manage a patient. They decide based on signs and symptoms if a patient needs further investigation, which can include an echo. Really the goal there is not to make it complicated, but to make it simple. Right? Allow physicians to make the clinical decisions that ultimately guide whether or not echoes are required. An echo is a fantastic tool. Right? It's one that we think is great. It's valuable to have a firm treatment target, like gradient, for instance, that ultimately is highly correlated with outcomes. The challenge has been the number of regimented echoes that are required and, honestly, the lack of utility for many of those echoes. That's an area that we really want to push the ball forward. Yeah. Makes sense. I do want to talk about, again, phase III regulatory path and some other competition, but maybe just to touch on it quickly on the non-obstructive side of the coin. Like you mentioned, there's arguably more white space here. Maybe it'd just be great to understand sort of the ACACIA-HCM data, what you think of those data from an efficacy and safety perspective. As you think about your differentiation, is it more on efficacy? Is it more on safety? Is it on both in terms of where you think you can move the needle? Sure. Maybe I'll speak to our data and allow you to put it in context, James. What we observed in the phase II study was very encouraging. This was a placebo-controlled study, 28 patients per arm, 12 weeks. Those patients are now in an open label extension as well, and we'll be able to share that data next year. What we observed was that patients had rapid and deep reductions in key serum biomarkers of HCM, in particular NT-proBNP, which is a marker of heart failure, and troponin, which were deeper and faster than has been observed. The second point there that's important is we saw dose-dependent normalization of NT-proBNP. This is a biomarker that's often used to rule in relative heart failure, so over 40% of patients who got to 60 mg, which is the highest dose, had normalization of NT-proBNP, which is notable. The parameters that we saw on echo were tremendously encouraging. I say this because when we've done our market research and we speak to physicians in a blinded way about what clinical parameters would lead them to choose an agent, improvements in diastolic function and structure are what we consistently hear as one of the greatest drivers of physician decision-making because certainly they want their patients to feel and function better, but this is a structural disease, as is obstructive, and to date, we've not seen huge improvements in the structure of this disease other than the data that were generated for BHB-1893. What we observed there were normalization of diastolic parameters such as septal and lateral e', large improvements in left atrial volume index that were dose-dependent, as well as significant improvements in left ventricular wall thickness, really notable over a 12-week period. We also observed that there were improvements on an absolute basis in KCCQ of roughly 18 in the high dose group, was dose-dependent, and placebo-adjusted 5.5 points at 12 weeks, so again, at an early time point. What we believe is that with further time, those effects will further consolidate. I think we found the data to be very encouraging for a potential best-in-class profile, and we're looking forward to generating global phase III data to support that. Yeah. Makes sense. I think one question just coming out of ESC, and sort of the question is if it's like a class thing, is from the detailed ACACIA-HCM data, was the heart failure cases and specifically the not ejection fraction-related heart failure cases. It seems like it's potentially just hemodynamic-related in the titration of these drugs. Just curious on your perspective, and is that something that matters or you're thinking about for this broader class of drugs? Yeah, just be curious what you think, because I feel like that was the one learning that people have had recently about these drugs and HCM. Yeah. We certainly continue to hear discussion in the community about risk versus benefit, right? I think one thing that's also notable about BHB-1893 is that this rapid onset of action that we saw in obstructive, we also saw in non-obstructive in terms of reductions, for instance, in NT-proBNP. We also believe that as a result of that this will be an agent that requires minimal titration. The phase III design that we're proposing and initiating would have, at most, a one-step titration as well. I think what was interesting to your point is many of those events were seen in the prolonged titration phase, and we think that we're going to be able to further simplify need for titration. Yeah. Makes sense. Awesome. Well, yeah, like you said, a lot of data, ways to differentiate even on efficacy and safety, but also convenience, dosing, etc. I guess, underlying all of that, the other natural question here is the phase II data were generated by Hengrui in China. Just sort of what's your confidence in those data extrapolating to a more global population, and what have we seen with the other CMIs and, again, what kind of gives you confidence there? Sure. D ata that's generated in different geographies is very common across our industry. Most studies now are multinational. There's a few key factors when you think about data that's been generated in other geography as to the relevance, as you put it. I'll mention a few. One is whether or not this is a disease that the biology is similar across geographies. In the case of HCM, it is, and HCM in China, in Japan, in the U.S. is HCM. In obstructive disease, certainly the second point that's important is that there's historical data demonstrating across geographies for the CMI class similar responses. We've seen similarities in terms of the response rates, for instance, across geographies with one important point, which is that gradients are often higher in the Chinese population, and that's typically a harder to treat population. The third is that the standard of care is very similar. The baseline medications that patients are on, which in obstructive is largely beta blockers and calcium channel blockers, is similar, and that is what we have observed and are observing is a similar rate of background medication use. Unfortunately, there are not many options for patients, and as a result, there are not many treatments that are used other than beta blockers, CMIs, and surgery. What is also important is whether the PK can be generalizable. Given that there are not strong CYP liabilities and that there is a mixed renal and hepatic clearance here, we had a fair bit of confidence that this would be similar. We have confirmed that in healthy volunteers in an ethnobridging study in Australia in Caucasian patients. Overall, these data taken together give us a lot of confidence. The final thing I would mention is that we have a very high-quality partner and sponsor in Hengrui. I think tremendous organization in terms of quality and speed. In addition to that, as we were really looking at bringing the program in, we went a step further, which is to actually send a central reader to China to over-read a majority of the echoes, and that gave us further confidence both in the magnitude of treatment effect and safety, but also in the baseline characteristics of those patients. Yeah. Makes total sense. That is really helpful, and I think looking ahead to next year, obviously sort of the key catalyst or key focus both on the obstructive side or main ones on the obstructive side in terms of the Hengrui phase III, you are going to have your interim analysis from your obstructive study. In the context of that, and this kind of extends beyond the sort of a Chinese discussion, is that you think maybe the Hengrui data might be able to serve as sort of that plus your interim as an early sort of filing path on the obstructive side of things. Maybe just kind of help us give a little bit of the context around that and sort of help us understand your confidence and sort of how you are treating that. You are treating what is your base case. Is it that, or do you need to run the full study? Yeah, just be great to hear your thoughts and then specifically what you have heard from the FDA about the Hengrui data. Great. I'd say first that we'll be excited to be presenting the one-year data from the phase II study, which now all 42 patients from that study treated out to one year, including repeat cardiopulmonary exercise testing after washout and then again at one year. I think those data will be an important catalyst for us at AHA this fall. Our partner, Hengrui, has been executing very well on the phase III study, and we have a lot of confidence in the quality of that study as it was designed and how it's being executed. We've been equally executing well. We have multiple sites active for LIONHEART-HCM, our phase III study. We also have patients being screened. We're now in a place where we're fully active in that phase III program and moving forward at pace. To your point, we've had very positive interactions to date with regulators around the notion of using an interim analysis of our study and the full data set from the Hengrui study as an initial filing strategy. As always, there's risk on any filing strategy, and certainly the relevance of that complete data set will be a matter of review. However, we did receive very detailed feedback, including a request to include PK from patients of Asian descent in our study to be able to directly compare not only PK in healthy volunteers, but also patients. The feedback was detailed and collaborative, is the way I would put it in terms of this filing strategy. Okay, great. Makes sense. In terms of non-obstructive, what's the timeline for that phase III to be up and running? We've indicated that we will be initiating it early next year. Reality is that we are moving forward equally at pace in that study. Okay, great. Maybe just one last question, because I think, again, one of the other key focuses in just the HCM space is on the competitive front is Edgewise, and they just recently disclosed their new mechanism or their mechanism. Just curious what you think of Edgewise and their positioning relative to some of the data you've generated and, again, just your position in the competitive landscape here. Sure. I will speak to our data and also speak to the market, which is that we think this is a very large market. I am an IBD doc by training. I could not have imagined how many different mechanisms ultimately have been commercially successful in that market. We think it is a market that moves from being an incident to a prevalent market in terms of patient starts. We feel quite confident in the efficacy and safety profile of BHB-1893 to date being a highly differentiated option for patients and one that could have significant penetration into that end market. Yeah. Makes sense. Then maybe just last question, actually, Paul. In terms of runway kind of post-IPO, what does it kind of get you guys through in terms of catalysts? Yeah, our adjusted cash balance from a Q2 perspective, assuming the IPO proceeds, is north of $520 million. That raise was really to fund both those phase III programs, the LIONHEART-HCM and the NOBLEHEART-HCM, through data readouts, as well as supporting early pre-launch planning activities. Okay. Great. Well, we're about up on time. Travis and Paul, thanks for joining, and thanks everyone for listening in. Thanks, everyone, and thanks for having us, James. Appreciate it.