Good morning. My name is Keay Nakae. I'm the Director of Research at Chardan and one of the Senior Biotech Analysts. It's my pleasure to introduce our next guest from Orchestra BioMed, founder, chairman, and CEO David Hochman. The format for this session is roughly a 25-minute fireside chat. As a reminder to attendees, if you'd like to ask a question, please type it into the question box under the video player. With that out of the way, David, thank you so much for joining us today. Maybe to start, can you spend a few minutes providing an overview of Orchestra for audience members who are new to the story? Sure. Orchestra is a biomedical innovation company that's focused on leveraging strategic partnerships to advance and commercialize high-impact medical device therapies. We have two platform technologies: our AVIM therapy program, which is a treatment for hypertension, a potent treatment for hypertension that's delivered through a standard implantable pulse generator or pacemaker as firmware programming. We treat hypertension in high-risk populations, and we're partnered with Medtronic. Our second program is called Virtue Sirolimus Angio Infusion Balloon, built on a platform of novel delivery of an extended-release proprietary formulation of sirolimus. The first construct is an angioplasty system, or what we call an AngioInfusion system for the treatment of first coronary and broader peripheral artery disease. We're partnered with Terumo on that program. Both programs address established multi-billion dollar markets, significant unmet needs. Our job is to execute and deliver on pivotal trial data. Our partners would take over, file for regulatory approval, and ultimately commercialize these products worldwide. We make money through significant royalty or revenue share stakes with these partnerships. Our business model is designed to be capital efficient, focused on clinical execution, and ultimately leverage the enormous resources and distribution of globally established world leaders in key markets. Great. Maybe let's start with BACKBEAT. This is a device therapy for hypertension. You have a lot of data to date from studies in human, and this has been advanced into a pivotal study. Maybe can you quickly summarize the findings from your prior clinical studies? Sure. The therapy that is now being studied in the BACKBEAT global pivotal study is called AVIM, or Atrioventricular Interval Modulation Therapy. What we're able to do with AVIM is significantly lower blood pressure. We do that immediately. It's a substantial effect and persistent by using an established device, a dual-chamber pacemaker, to modulate the timing of the atrioventricular contraction, reduce cardiac preload, and then modulate cardiac afterload and sympathetic activity, and produce a long-lasting, actually persistent effect on blood pressure. We've done multiple prior studies, as you mentioned. Our most recent study was the MODERATO II double-blind randomized study. This was our think of it as if you're looking at this like a drug. This is a digital drug, our phase two study ahead of what we're now doing, which is our pivotal. In that study, we showed and the gold standard for looking at blood pressure reduction is 24-hour ambulatory blood pressure monitoring. Essentially, we showed an effect of over 11 mm reduction in 24-hour ambulatory systolic blood pressure in patients at our six-month endpoint. That was highly statistically significant and superior to the control group, which showed only a 3 mm reduction. That type of reduction, 11 mm reduction in systolic blood pressure, particularly in these are patients that are in their 70s. They already needed a pacemaker. They had significant hypertension and comorbidities. That type of double-digit reduction in systolic blood pressure corresponds with probably a greater than 30%, particularly for an older population, reduction in risk of heart attacks, stroke, progression of heart failure, progression of end-stage kidney disease, and death. Very significant blood pressure reductions with an outstanding safety profile. Actually, we had no major adverse cardiac events in our treatment group in that study. Given your approach to treating hypertension, certainly the data you have to date has informed the design of the ongoing pivotal study. Yet at the same time, you're plowing a lot of new ground here. There's always going to be some unknowns. I guess with that in mind, you did implement some changes in your protocol to the ongoing pivotal study that you began to implement last fall. First, I guess maybe to start, why did you do this? Why was this proving to be a more optimal way to evaluate the patient population? We created AVIM therapy. We developed this from concept stage. It's an asset that's wholly owned by Orchestra BioMed, our patent estate. I think a year ago, we provided an update, 110 issued patents. It's a larger estate by now. We really pioneered the ground and brought this capability to the market. All the studies we've done, including our pivotal study that we're now running in collaboration with Medtronic, we've had to pioneer the study designs, learn from how pharmaceutical studies are conducted in treatment of blood pressure disease, and also learn from other device-based therapies. Ours is unique. We have no direct competition. Part of that is learning how to here we're working with implanters of cardiac rhythm management devices, pacemakers. We're dealing with patients they deal with every day. We're helping to learn with them and teach them how to do the workflow, evaluate blood pressure, find the patients that meet the criteria for the study, and ultimately use the benefits of the therapy and the study design. When you're doing something for the first time, that can be quite impactful, really, in our view, change the landscape of blood pressure management and ultimately risk management and prevention of major events in older comorbid patients. You have to be willing to make the investments alongside your clinical investigators and here with our partner, Medtronic, to learn how best to do that. We've made adjustments. We've really taken advantage of the fact that for the clinical study, this therapy literally can be downloaded as software into an implanted device. Part of our change is just expanding that window with the support of FDA to more patients, a longer look-back window, a longer look-forward window. That has really made impacts as we have gone forward on making enrollment in the study more predictable. FDA has been a great partner. They actually recently, last week, we announced that FDA granted breakthrough device designation to AVIM therapy, which we think has significant implications as to the addressable patient population, as to potential additional reimbursement. It is important to think about, as you are pioneering a new therapy, how to work with the agency, work with your investigators, and learn the lessons that you have to sometimes learn as the first mover and innovator in a new space. Great. Again, given the focus of today's topic being interaction with regulators as you advance product development, can you describe how you did work with regulators in this case to affect this change to an ongoing clinical trial, just to ensure that you did so in a manner that did not compromise the statistical integrity of the trial? Sure. Everything we've done with FDA is based on science and based on clear communication and interaction. We have, I think, a distinct advantage in this program of being partnered with Medtronic, who is the global dominant market leader in cardiac pacemakers and cardiac rhythm management devices. Medtronic was founded around the pacemaker technology. In interactions with the agency, we work closely with Medtronic, the BACKBEAT global pivotal study is being run with our technology, but on Medtronic's commercially available devices. The original IDE required collaboration with Medtronic, really submission of data on how the algorithm was running alongside the proposal for the clinical study. We've had a great relationship with the FDA with respect to the protocol. We actually identified some of our concerns and what we wanted to adjust pretty early. Really, in the first quarter, we activated the study. FDA was responsive interactively and approved the protocol amendments. It does take a lot more time to roll those out than just the FDA approval. You need to work with all the individual sites. That went well, as did our breakthrough designation submission here this year. That submission went in Q1. We received the approval exactly on the statutory timeframe from FDA. There was great interaction with FDA, thoughtful questions. They reviewed our data. They reviewed our proposed indication for breakthrough. They shared their opinions. We really arrived at what we thought was a great indication or breakthrough designation for a population that we measure is just under 8 million patients in the United States that meet the increased risk profile and that suffer from uncontrolled hypertension despite medical therapy. We see breakthrough. We see the protocol changes. We see all our interactions with FDA as part of our responsibility to foster great communication with the agency so that they can do their job and ultimately work with a sponsor like Orchestra, along with a partner like Medtronic to help us assess this technology and evaluate in the right study, which is what we're doing. Maybe let's just dive into the value of having a partner like Medtronic, which obviously possesses extensive experience and knowledge of how to successfully interact with the FDA and other regulatory bodies. As you've mentioned a couple of times here, David, these are relationships. These are individuals that you interact with at the FDA. How valuable has it been to have a partner like Medtronic? Tremendously valuable. The individuals at Medtronic that manage their regulatory relationships are highly experienced, knowledgeable. Medtronic has an array of approved devices in this category, from pacemakers to implantable cardiac defibrillators to cardiac resynchronization therapy. They interact with the FDA on a regular basis, actually need to have regularly scheduled calls to monitor activities with commercial devices. Certainly, we think because we're working with them closely, we're partnered for the long term, and we're running this trial on their device, it's a big advantage. Our interactions with the FDA are done collaboratively with Medtronic. We are the sponsor for the trial. It's our trial. It's our intellectual property, but this is an important partnership. I like to talk about having a partner like Medtronic that both invented the pacemaker and is the global leader. In the United States, actually, and controls more than half of the market for pacemakers is priceless. It's really a tremendous leverage for an organization like Orchestra. Obviously, what we bring to the table has enormous value too. We invented the therapy, created the patents, developed the original data you referred to, and now are hard at work to get the final pivotal trial data over the next year so that we can have data that supports approval and ultimately adoption of this therapy, both for pacemaker indicated, but based on the breakthrough, a much broader population of patients that really is at significant risk of morbid and mortal events, the events we all worry about, heart attack, stroke, heart failure, that our therapy, we think, can make a big difference in preventing those events and slowing progression and really making older higher-risk patients healthier for the long term. Yeah, I think that for Orchestra, the partnership with Medtronic for BACKBEAT cannot be overstated. Before we move on from BACKBEAT, let's just briefly touch on the breakthrough device designation you just received. I guess beyond the accelerator review, maybe talk about some of the secondary benefits that you see as being associated with this designation. Sure. I might share a slide here from our corporate presentation that we provided an update on, if I can get there, last week. I think it's important to note what the designation was and what it means for a population. The breakthrough designation, we're running the BACKBEAT pivotal study in patients that have all of these characteristics, but they already have an indication for a pacemaker. That's allowing us to sort of maximize the risk-benefit and facilitate enrollment without having to ask a patient to get an implant just for the AVIM therapy. Fundamentally, those patients and the patients that the breakthrough applies to, they have uncontrolled hypertension. Despite the use of antihypertension medications, they may have tolerance issues. Those medications have adherence and tolerance issues. Patients have increased 10-year atherosclerotic cardiovascular disease risk and preserved left ventricular ejection fraction. When we looked at that definition and we carefully sourced references to really try to understand what's the population of patients that fits within those characteristics. The broader population in the U.S. is just over 7.7 million patients that have all of those characteristics. Within them are key subpopulations, patients that are older that have what's called isolated systolic hypertension and/or diastolic dysfunction, likely both of those things. We've shown great data from our prior studies being able to treat ISH, being able to actually reverse the course of diastolic dysfunction. That's almost 2.5 million patients that we believe we provide potentially an optimal targeted therapy. A smaller, but even more high-risk population are patients that have hypertension despite meds, but also have heart failure with preserved ejection fraction. HFp EF is a huge problem that remains inadequately treated with either drugs or devices. This is about half of that HFp EF population in the U.S. As you can see on the left, that's the patient population with hypertension and a pacemaker. That's about 300,000 that we're focused on for the BACKBEAT study that our current partnership with Medtronic gives them exclusive rights to. The overlap of these images is really important because the characteristics of the broader population are seen heavily in that pacemaker population. What we're excited about is the study we're running now is generating and is going to generate clinical evidence on this whole population, but focused, once again, on the pacemaker population. We think the breakthrough really reflects the opportunity for AVIM to benefit. By the way, it's still less than 7% of the whole hypertension market in the U.S. Targeted higher-risk patients that really their blood pressure is driving serious events or serious progression to conditions like heart failure, which are the most expensive and dangerous conditions in healthcare. Breakthrough really reflects the broader opportunity. Importantly, breakthrough designation also translates into big advantages if we at Medtronic choose to pursue add-on reimbursement for AVIM therapy devices. Our current partnership gives Orchestra a very significant revenue share, up to $1,600 on every device, assuming no changes to reimbursement. Breakthrough creates a pathway to make add-on reimbursement very possible. That is exciting for us as well. Let's move on to your second product candidate, which is Virtue SAB. That combines a drug with a device and as such requires a more complex FDA review involving multiple divisions. Let's dive into that a little bit. I guess the question I have is, how does the agency determine which division, whether CDER or CDRH, takes the lead? Is there advantage to the sponsor if it's one over the other? If so, why? Very interesting question. First off, let me point out today we had significant news related to Virtue SAB. We received an IDE approval of an amendment that we thoughtfully put together of our previously approved IDE to now conduct our pivotal study as a head-to-head study versus the only paclitaxel-coated balloon that's approved for coronary use in the U.S. A big win for us today. Really the product of, I think, a great relationship that we built over time with the agency. As you said, this is a combination product device. The sponsor, we have a choice as to what is a pathway. Do we want to be principally a device or a drug? In this case, our product does two things. It performs balloon angioplasty. That's really the mechanical expansion of a blocked artery to restore flow and essentially unblock the artery. Virtue delivers what is really the gold standard drug for the treatment of then restenosis, reclogging of the vessel. That drug's sirolimus. We do so in a novel way. We do so with an encapsulated extended-release formulation we developed. We do so without coating the balloon, really delivering a large liquid dose that allows us to actually meet and actually exceed what has been the established profile of drug delivery in the most successful previous devices, sirolimus or limus eluting stents. Your question is important. We had to choose for that particular configuration of the product. We have pipeline configurations that are different to be a device, but also to submit a drug master file and to be reviewed heavily by the drug division that wanted to understand and help the device division understand, you know, how does this formulation work? What is it doing uniquely? That was a relationship we built over time. I think this IDE approval really showcases how well. I'm super proud of our team for the correspondence with the FDA, all of the submissions. It's important for people to understand regulatory submissions are often thousands of pages and require substantial effort to produce the preclinical and clinical efficacy safety data supporting approval. This one is complex, but it's complex for a good reason. Our product is different, we think, better than other products in the category and fundamentally is going to offer value to patients and physicians that makes the complexity of the regulatory interactions also very much worthwhile. The success of an approval like we announced today, very satisfying to allow us to take a next step now to a pivotal trial. Great. You mentioned this morning's news about the IDE for the pivotal study for Virtue. You'll now be looking at a non-inferiority study against Boston Scientific's AGENT drug-coated balloon, as you said. Obviously, this was necessary given that you have a competing product that's available commercially that is going after the same patients. I guess beyond addressing ease of enrollment with the protocol change, talk about how this design could actually be advantageous to you folks. When you believe you have a best-in-class product, which is what we believe, you want to take your pivotal study to be able to showcase that product. You want to do so, though, in a smart design that gives you optimal probability of regulatory approval and success. We think this head-to-head study that we're now approved to execute is the best pathway to do both of those things, to one, ensure regulatory approval, but also hopefully differentiate and showcase the product that we have. I can share a few more slides because I think it could be helpful. Virtue is really built to be different than every other product in the category, which are drug-coated balloons. We focus on delivering a drug, sirolimus, which is really effectively on every drug-eluting stent. The data I'm showing you on the left showcases why our system is powerful. The orange line shows the known therapeutic concentration of drug. The orange boxes show our very large published series of animal data showing we can deliver a huge payload of that drug well above the known dose because of our novel system and doing so without a coating on the balloon. We do not lose drug in transit. Physicians do not need to rush. They do not need to worry about particulate. Our drug levels have been shown to be these are protocols not done at the same time with the same animal models. We can deliver more drug than proven stents. Here you are seeing Cypher and Xience is actually Abbott's number one stent. We actually have a system without a stent, leaving nothing behind that delivers more drug. That has produced best-in-class data. The data here is measured by what is called target lesion failure. Target lesion failure measures, did you need to re-intervene or did you have an adverse event in a patient? 2.8% at one year is an outstanding result in coronary in-stent restenosis and compares favorably to what we've seen in a similar population from Boston Scientific's AGENT paclitaxel-coated balloon data where their TLF rates in first layer restenosis were 13.5% in year one and continued to rise. Ours did not. Fundamentally, we believe that a head-to-head study allows us to, one, prove non-inferiority. That's the threshold we need to prove. We're very confident in being able to demonstrate that. That means we have this very highly probable pathway to regulatory approval. That's how you get on the market. In a head-to-head study, we also will look at the results and be able to see how our product performs in the same patient population in a prospective study against now the only product available on the market, the market leader. Boston's done an exceptional job with AGENT, but obviously, we believe over years we've built a better solution. We think this trial can do both, get us approved, but also showcase those differences and advantages. Great. Let me ask you about your interactions with the FDA. A lot of people have been worried with the workforce reductions. There's no live bodies there anymore. I think your recent breakthrough therapy designation and today's news about the IDE would maybe give you a position to at least weigh in with an opinion about what's going on from your perspective in terms of sponsor-agency interaction. I think that so far, 2025 has been our best year of interaction with the FDA. I can only say good things on behalf of the Orchestra BioMed team about what it's been like to work with FDA in the current environment. Interactions have been on time. They've been thoughtful. We've seen continuity. We have two different review teams, two different programs. We've seen continuity with our reviewers. We've seen responsiveness. We've seen thoughtful interaction. Most importantly, we secured the designation we were looking for and the approval we were looking for really exactly on time. We're right on time with what we were looking to accomplish and looking now to maximize the impact of those approvals. So far, this FDA is working as well as, and in some ways, even better than we've experienced in the past. Certainly, there's been disruption. We've had our concerns. The empirical evidence for Orchestra is that FDA is functioning very well. Most importantly, we're controlling what we can control. Our team's done an excellent job. I just want to take this opportunity to really call out the Orchestra team with regard to the breakthrough designation, also the Medtronic team. You can only work so well with the FDA if you need to be able to respond to their timelines. Oftentimes, they ask you for information on a tight timeline. We did a great job of providing the information needed thoughtfully, accurately. I think it shows in the results that we've been able to share through two announcements we made in the last two weeks. We think those announcements bode very well for both programs. Obviously, the Virtue announcement puts us on a path to, in the second half of this year, initiate the pivotal trial. We think the trial will go well and we're confident in the results. With regard to the AVIM program and the breakthrough designation, as we talked about, really highlights the broader population we can serve that's a significant high risk with significant unmet need population and provides a clear path to potentially higher reimbursement, higher revenue for Medtronic, and obviously a higher royalty stream for Orchestra BioMed. We are thrilled about where we are from a regulatory catalyst standpoint. That's why I was excited to talk to you this morning. We booked this a while ago, but you don't know that you're going to have real deliverables like we do to have just in time for a discussion like this today. Great. We've reached the end of our time for this session. David, thank you so much for joining us today. Hey, thank you very much. Great to be here.