Good morning, everybody. Very pleased to have with us today David Hochman, Chairman, Chief Executive Officer, and Founder of Orchestra BioMed. And my name is Matt Miksic. I cover medical devices here at Barclays. Welcome again. Thanks. To the conference. Great to be here as always, Matt. Well, thanks for coming. So, you know, I thought we'd sort of switch things up, I guess, given some of the focus on Drug-Eluting Balloons (DEBs) in the coronary this past weekend at CRT and some of the progress you've made in the last 6-12 months there. Before we get started, I thought it might just be helpful for you to give kind of an overview of the two programs, where you stand. Sure We can kind of get into a little more detail. I'll try and be succinct. For those that don't know us, Orchestra BioMed is a biomedical innovation company focused on two right now, two pivotal stage cardiovascular programs. When I say pivotal stage, we're enrolling both of our pivotal trials for our drug-eluting balloon, Virtue Sirolimus AngioInfusion Balloon (SAB) for coronary artery disease. We started that trial just now about a quarter ago, a little more than that. We have our other program, Atrioventricular Interval Modulation therapy or AVIM therapy to treat hypertensive heart disease in high-risk patients, starting with the pacemaker population. We're partnered with Medtronic on that program, and the business model is all about leveraging strategic partnerships. Our job is to get to pivotal data. Our partners will drive commercialization. We make money through significant royalty interests. That's what we're doing, and that's what we're focused on now. Two really exciting technologies in big markets and enrolling a lot of patients actively. We're happy to be at that spot with an outlook towards finishing the BACKBEAT trial this year, having data hopefully soon thereafter. The Virtue trial, maybe a year or so behind that from an enrollment standpoint. A little bit longer on data just because the length of time of the primary endpoint. A lot going on at Orchestra. Yeah. Very satisfying. Sure. A lot of progress, including financing last summer. Yes which really, you know, given some of the uncertainty around Virtue and the negotiations with Terumo, really seemed like it ended well and positioned you to kinda get back into that program and force. Our team is so excited about having a strong balance sheet, but more importantly, having a balance sheet that was fueled by partners. Medtronic made an additional $30+ million commitment. We expanded the scope to think about leadless in the future. We resolved our partnership with Terumo, creating optionality for both companies and brought in another $30 million from them, and then brought in Ligand as a strategic capital partner, which I think some people didn't see coming. But Ligand in many ways was an inspiration for our business model and now really is a terrific capital partner, with a long-term focus, also with a royalty interest in our programs. Spent a lot of time with their team recently. Was in Boston with them last week, and just a really outstanding company that has a great perspective on, you know, why Orchestra is hopefully headed to great success. All that allowed us to also minimize equity dilution, but we also have great shareholders. Our financing was also fueled largely by existing shareholders. We're in a great spot with really a couple years of runway and ability to think long term about the next set of milestones. Awesome. Okay. I think the last few times we've met like this, we've talked a bunch about AVIM, but I thought given the success of AGENT in the marketplace, you know, I would say kind of validating the coronary Drug-Eluting Balloon (DEBs) market, but I'd say that was already sort of validated in Europe. Some of the other data that's been presented more recently. I mean, it just felt like CRT this year, this past weekend there was a fair amount of focus, TCT as well with SELUTION SLR data. Maybe talk a little bit about before we get into the specific recent events, you know, how Virtue is positioned, you know, to address these markets but is also different. Yeah than the platforms that are out there. Well, first I think because only Boston Scientific has a commercial coronary Drug-Coated Balloon, Paclitaxel-coated balloon in the U.S. I think, U.S. investors are still, you know, they don't break out the revenue yet, so there's still, I think, limited visibility to what we think is a huge growing paradigm shift in the treatment of coronary artery disease away from drug-eluting stents towards Drug-Eluting Balloons. Notably, every other product in the category other than Virtue is a Drug-coated balloon, either with paclitaxel, that's the majority. That's what Boston Scientific has with Agent. Medtronic has a program in a U.S. IDE study with a Paclitaxel-coated balloon. Most of the products available in Europe, and there's more than a dozen, several products available in Japan and other markets like China, predominantly Paclitaxel, a few sirolimus options. We can talk about that. The paradigm shift is super important, but it's really interesting. You're talking about a almost $8 billion market where I think if you talk to physicians and you were at CRT. First let's note, there were upwards of 70 abstracts and presentations on Drug-Coated Balloons at the CRT conference. While it's a great conference, that's a lot of content. Yes. I think it was the number one topic. What you see is a paradigm shift, but also a lot of kind of frustration or a view that these Drug-Coated Balloon products are not yet delivering the kind of data that I think the clinical community would like to see. Leaving nothing behind, not leaving behind metal in the artery now is, not just a hot topic, but an inevitable trend, we believe. Physicians want better outcomes, and I think the outcomes we're seeing with AGENT while opening up the market are similar to what we're seeing with other products. They leave a big gap. I mean, frankly, Drug-Coated Balloons don't perform as well in terms of target lesion failure as drug-eluting stents. Even in indications like coronary in-stent restenosis, we saw this from the SELUTION for ISR IDE data, which still hasn't published, but we're looking at the data from TCT. They had a standard of care arm, which was predominantly drug-eluting stents on top of drug-eluting stents. If you look at that data, you know, target lesion failure with a stent on top of a stent is pretty good outcome. You know, actually in single layer ISR was, I think, 7% or 8% TLF. Now the concern is metal on top of metal creates longer term challenges, and physicians now clearly would prefer not to do it. Right. Both with AGENT and with SELUTION and other products, it looks like you have residual target lesion failure in the teens, and that particularly those three-year AGENT data came out at CRT. There seems to be a benefit in year one, but that levels off and essentially equivalent to a plain balloon in year two and year three, and you have a climbing TLF. We're hearing very much as we're now engaging sites and onboarding physicians and educating physicians that want to come into the trial, and it's super high enthusiasm on how we're doing things differently and how that might offer a clinical advantage. Fundamentally, what we've done is taken the drug that is a gold standard, Sirolimus Rapamycin. We have in a proprietary fashion facilitated or encapsulated that to facilitate significant uptake of the drug and creating a local depot in the tissue and extended release through that encapsulation, which is novel. But we fundamentally deliver the drug differently. Instead of a coating that is a drug that is manufactured in a vial, we reconstitute water, we measure a dose relative to the size of the balloon or the lesion you want to treat. That dose is protected at the back of the catheter and is used actually as the inflation media for a microporous balloon. The physician literally controls and drives drug delivery when they're in position where they want to be. A lot more drug, it's liquid delivery of this proprietary formulation. A lot more drug gets to where we want to go. We've published, and this is rigorously done, preclinical pharmacokinetic data on a large sample size of animals that's been published of our 750 vessels. You're talking about a dose that is multiples of what a stent delivers on day one and maintains that advantage versus a stent over the 30-day critical healing period. Relative to Sirolimus-coated balloons, you're maybe a 40- to 80-fold increase in drug levels. They're well below a stent. That's all the difference. We know the drug can help heal the vessel if you get enough of it there and you can maintain enough of it. What we saw in our pilot results in single-layer and stent restenosis is a 2.8% target lesion failure rate. Our goal in bringing Virtue forward is to have, we think, a best in class and optimal solution, optimal product offering. I now can't really use the word solution in a sentence the way I used to. That's true. We have a competition in that regard. We think Virtue is an outstanding product that has the opportunity to deliver better clinical results. Now we're in a head-to-head trial, and we'll see those results, you know, in a couple of years, unfortunately. We're working hard to drive the study. Sure. No, that's exciting. I think, you know, from the sessions, you know, I think also the panel discussions around the choice of drug. You know, as you mentioned, sirolimus has become the gold standard. You know, that it's sort of like that decision was made a long time ago in the coronary. But as folks get into discussing it again and why, I mean, there's some very clear reasons why. So yeah, the setup of not having a polymer, using sirolimus, and being able to show that kind of bioavailability over time is exciting. Early, but exciting. Well, polymers can be problematic if they're the right ones. You have to make sure that you avoid polymers. We see with certain polymers, PLGA, PLLA, that can induce inflammation. That's what happened with the bioabsorbable stents. Those materials are still being used in some of the coatings that are emerging. I believe there's that type of polymer in the Cordis SELUTION coating. Our approach is, we've published this data as well, how we encapsulate the drug is a novel approach with novel materials that are known, but there is no polymer degradation in our system. We've demonstrated elimination of all that. It's really about how you release the drug in a unique way. Virtue is, I think, that next generation and we're seeing the enthusiasm from physicians. They understand. There's a lot of education. How does Sirolimus work? How does Paclitaxel work? Do physicians really understand the difference? Paclitaxel has reemerged on the scene because of drug-coated balloons. The difference between that as a cytotoxic agent versus Sirolimus as a cytostatic agent, when you're really trying to heal a vessel by managing proliferation, is something that, you know, we're still doing a lot of education on in terms of going back to the data, the mechanisms, what we've seen in stents, and why this is such a differentiated program. A lot of what our team was doing at CRT was meeting with physicians that wanna be in the Virtue trial, training them on our product and, you know, educating them on the data we have and why this product is designed the way that we designed it, what it's supposed to deliver for them and for their patients. The interest is, for a small company, that's a lot of demand and interest. We won't have a hard time getting physicians on board and sites on board. Now it's really about selecting the ones that fit best with our ability to support. That's a great place to be. We always felt we would be in this moment. We've been at it for a while, and so it's great to actually be doing it and have the market ripe for what we believe we have. No, it's great, too—and congrats on the progress in the last year, mostly in terms of, I guess, just positioning, partnership, you know, financing, and then being able to move forward. Even though I'm sure there's a lot of other work that we didn't see going on behind that. Maybe, given that that's a couple of years away, you know, back to AVIM, which was probably- Sure The main topic that you and I have talked about, just because that's the trial that got started, that's the product that's, you know, expected to reach the market first. Mm-hmm. Can you talk a little bit about how that's going? Yep. The trial, which I'll acknowledge has been challenging to maintain the timeline, is going as well as we could have hoped at this point, relative to some of the challenges we have overcome. The protocol changes we made are working. We've expanded the site footprint now to north of 100 sites. We can go up to 130, and there is a clear demand from sites globally to participate. Having more centers, having a much more flexible protocol for enrollment, really having our full team in place, having all the support that we could ask for from Medtronic, been a phenomenal partner. We're now seeing enrollment acceleration that we've been looking for. We'll probably just given the importance of aligning with Medtronic on every detail, I think next quarter is when we expect to provide more of a high specificity timeline. Investors are really interested in when they'll see data and what happens next in terms of Medtronic filing for approval and the commercial outlook. We hope to provide those updates, but I'm really excited about the progress and congratulate my team. I've also put my leadership team's put a lot of effort into that process of selecting and engaging and onboarding sites and really driving enrollment. The thing about AVIM that's so exciting is it is a unique treatment for high blood pressure. You activate that treatment through the pacemaker programmer, just like anything you would do with a pacemaker, and you see blood pressure drop right away. If you remember, the trial design requires us to set up AVIM. We download it into the patient's device. We set it up in all of the eligible patients, and it needs to have a threshold response in those patients of at least five millimeters to qualify for randomization. That's the vast majority of patients. You're seeing your therapy working, and you have to calibrate it, make sure that we drop blood pressure, not too low. These are significant double-digit drops most of the time in patients. Our previous trial, you know, we saw that same thing. Set up, it works. At three months, you have great double-digit ambulatory results. We're going into the work now with a lot of confidence. We need to bring on board the patients, but we are confident in the data because we see the therapy working right away. These are patients where if you can get their systolic blood pressure down 10, 15 millimeters of mercury, what we showed at CRT, Daniel Burkhoff presented, an amalgam of data, what our principal investigator, David E. Kandzari, showed at THT the week before, is we're talking about patients that are older, have high risk. Many of these patients have isolated systolic hypertension, diastolic dysfunction, and we've expanded the enrollment to at least Class II Heart Failure with preserved ejection fraction. The presentation of data really shows a significant benefit, not just blood pressure, but on cardiac workload, cardiac function, improving ventricular function. This is a game changer for patients that otherwise are gonna struggle to maintain compliance to medication, that have significant comorbidities and risk. We're really excited about the data, the trial, and more importantly, where Medtronic can go with the therapy, certainly within the pacemaker population. You know, we've actually been looking at our market numbers. Our estimate is there's probably one million patients worldwide getting pacemakers every year that have hypertension, because of the growth in the market, particularly out of China. That's an incredible patient population for a therapy that works with the device that they already need. Yeah. Pretty excited about what lies ahead for the VACI trial and for the AVIM program. Just to you know, folks that had not maybe been paying as close attention, some of the wider protocols, the expanded centers, being able to look back. Yep to patients who had received a pacer and then activating the therapy in those pacers. Those are some of the things that have helped kinda move enrollment along. Can you talk a little bit about the follow-up? Because sometimes we, Most of the primary endpoints of the study are at three months. Once we finish enrollment. It should be a reasonably quick turnaround of data, but obviously we're gonna wanna scrub and make sure we have quality data. We have a obviously the market leader as our partner, so that's part of what we're doing now is working closely with them on what was by design a handoff of responsibility. In our partnership with Medtronic, they are responsible for making the device. They are gonna have AVIM as a firmware integration to their next launch, which is coming next year in terms of transvenous pacemakers. They are responsible for the regulatory, manufacturing, and you have the world's dominant player in pacing for both sales, marketing, clinical support. We have a significant per-device royalty that we've talked about. I mean, we're excited. We think this is a huge opportunity for Medtronic. We and Medtronic are going about everything very thoughtfully in terms of how this can become hopefully a standard of care for those patients. Given the promise of the data, there's an opportunity to expand that collaboration to what we think is a market that could be four or five times as large using the therapy in that known device in patients that have a similar profile but don't yet have an indication for a pacemaker. What's interesting about the changes in the clinical study though are it really is going to now reflect what we think is the real-world application of the therapy. By looking at patients that have had devices going back as far as six years, looking at new patients, we'll be able to see how AVIM therapy could be used over that 10, 12 years of an implant. You put a device in, usually it's hopefully 10 years of therapy from that device. The trial now is gonna look at the impact of AVIM therapy across a spectrum of patients. I think that's gonna really help in terms of understanding the potential in driving clinical interest, patient interest in making sure if I'm getting a pacemaker that, you know, I have access to AVIM therapy over that 10-year period. If you don't put the right device in, you won't have access to the therapy. The trial, I think, changes are helping with enrollment, but also gonna really help with having the data set that really defines how this could be used to impact patients and benefit patients. Oh, that's great. I know you're not giving specific point in time predictions for follow-up and things like that, but just kinda stringing together enrollment complete, three-month follow-up. I think we had talked about revenues potentially for this product in late 2027, but really maybe 2028 being the liftoff. I think we're confident that 2028 is the year where Medtronic should have the opportunity. The trial is a global trial. Yeah. The last sites that are gonna onboard are gonna be Asia, Pacific, Australia, New Zealand, a handful of sites that are excited to come on board. We'll have data globally. Medtronic's gonna leverage that data, assuming, you know, we achieve our endpoints as we anticipate for U.S., European, China, Japan, really global approvals. That should happen in a sequence. That's some of the things that we're gaining insight into as they now have line of sight to. It's a long lot of work and a lot of time needs to be put into a therapy and product launch like this. It's an exciting time to be now working with the market leader as they are adding precision and specificity to some of those plans. We obviously wanna share that with our investors, but that will come as we progress. Got it. 28 feels like achievable for initial commercialization. Likely their primary focus is gonna be on getting the U.S. market open. Still is their, you know, key revenue contributor. Okay. You mentioned, you know, the impact of hypertension on comorbidities like heart failure. Obviously, if you get folks down, get their pressure down faster, that sort of area under the curve has all kinds of implications for other ailments, heart-related ailments. It's not just fast. It's about sustaining that blood pressure control with confidence. This is a therapy that runs in the background. It's always on. The patient may be taking other medication, but this will reduce the compliance and adherence burden. It will be the primary, in our view, driver of blood pressure reduction. We know that if you can reduce systolic blood pressure by 10 millimeters of mercury, this is for the whole population. That's a 20%-30% decrease in relative risk of heart attack, stroke, progression of heart failure, progression of end-stage kidney disease. In a 70-75-year-old, someone of that age group, you're talking a much more pronounced risk. Particularly worrying about the relationship between high systolic blood pressure and stiffening ventricles, stiffening vasculature, driving not just events, but the heart failure risk. We think this is hugely important. Just think about HFpEF, which is still viewed as I spent a lot of time at THT. It's really the unconquered frontier. Right. In terms of cardiovascular healthcare. We'd estimate that there is over 1 million patients in the United States with diagnosed HFpEF with uncontrolled systolic hypertension. That is a unique population for a therapy like AVIM, where your primary approach is really lower the blood pressure. Your secondary benefits are gonna be all the things we worry about in heart failure. You know, ventricular size. You're gonna be worrying about, you know, cardiac function. We think we'll have an impact on quality of life. Can we have an impact in exercise tolerance? The primary endpoint is still gonna be focused on blood pressure, which we know AVIM does an incredible job, when you turn it on, but always on in terms of maintaining blood pressure. That is, that's an exciting point to be in. We're really, I guess now, kind of beginning to gain some real confidence around the timeline, more importantly, what that data's gonna show and what the potential is gonna be for the therapy, after. Well, we're at time, so that's a great place to stop. Thanks. Thank you, David. Yeah, I really appreciate it, Matt. All right. It's always great to be here.