Braveheart Bio Stifel 2026 Virtual Cardiometabolic Forum

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.

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.

For 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.

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 nanograms per ML 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.