Okay, great. Thanks everyone for being here, and welcome to the Wells Fargo Healthcare Conference. My name is Yanan Zhu. I am one of the biotech analysts here. It is my great pleasure to be joined by the management team of Atrium Therapeutics. With me here today are Kath Gallagher, President and CEO, Brendan Winslow, CFO, and Steve Hughes, CMO. Thank you for being here. Good morning, Yanan. Thank you so much for having us. It is really nice to be back. Great to see you. Great. Yeah. Great to be hosting the team. I was wondering, Kath, if you can start us off with an overview of the company and its formation. Thank you. Yeah, of course. I will get started, and then maybe Brendan, I will hand it over to you to talk a little bit about the formation. Atrium, we just passed our six-month mark. We were formed out of Avidity, when the Avidity, Novartis transaction happened late last year. Our focus and our vision is to profoundly improve patients' lives by pioneering RNA therapeutics for the heart. It is an incredible opportunity to really take the RNA delivery platform that we had had the ability to work on at Avidity and bring that to cardiac patients. As you think about how Atrium was set up, we were set up with funding, which Brendan can talk a little bit about as well, but more importantly, we have four programs that we are able to work on. The first two, we have our first one for PRKAG2 syndrome, which is going to be entering the clinic shortly here. We are in the final processes of just getting our phase I up and running to initiate our first patient. We have a second program in phospholamban cardiomyopathy, beyond that, we have two additional programs also for genetic cardiomyopathies. When you think about the cardiac space, there have been a tremendous amount of therapies for cardiovascular patients, but the rare genetic cardiomyopathy community has really been left behind, most of those patients today are treated with symptomatic management. For Atrium, this is an incredible opportunity to really pioneer that work, to really bring precision therapies to patients and actually target the root cause of their diseases. Great. You mentioned Brendan will talk about- Yes, I am sorry. Brendan. Yeah, happy to. Yanan, as you think about the impetus for the spin-out transaction with Atrium, you will recall that Avidity's portfolio consisted of both late-stage neuromuscular assets as well as earlier-stage precision cardio programs. I think with the spin-out of Atrium, it allows us to put our team's full focus in the precision cardio space, as well as continuing to progress our existing collaborations with Eli Lilly and BMS, which were assumed in the spin-out. As Kath mentioned, with our lead programs in PRKAG2 syndrome and PLN cardiomyopathy, these are diseases that have no approved therapies for their underlying cause of their diseases, we are going to be paving new pathways along the way, which as a smaller biotech, we are particularly well-suited for. Got it. Kath, I was wondering, can you talk about, because you have a long history with AOC, the platform. Talk about the suitability of this platform for cardiovascular disease. Absolutely. When you think about AOCs, what we are doing with them is we are using a monoclonal antibody to the transferrin receptor. What we are doing is linking that to an siRNA. Why that is really fantastic for the cardiovascular space is because while there have been a number of targets in the heart for a long time, they have been targets that you really could not access. The AOC platform really allows us to deliver, for example, an siRNA to PRKAG2 to the heart. AOCs in particular and the transferrin receptor, we really get a tremendous amount of— There is a lot of transferrin receptor in the heart. Because of that, our AOCs really have a lot of delivery there. You will even see, as we talk later about our dosing and our phase I/II study, that we do not have to use as high of doses, things like that, because of the fact that we get so much more into the heart. It really is this kind of twofold piece of the heart itself, it really has a lot of transferrin. It is naturally expressing it, so we are utilizing that natural biology to get in there. In addition, we can actually target the underlying cause of the disease and really deliver that siRNA directly to where we think will have an impact. Great. That is great to hear. I was wondering if you can also touch on the news from last night, from the DM1 study. Yeah, of course. Whether that has any read-through to cardiovascular or cardiac muscle targeted approach. Yeah. Let me answer your question by saying no, it does not have any read-through to Atrium. We're kind of full bore going on our programs. It was definitely not the outcome I think any of us were expecting or hoping for. And I'm really thinking about the community today because I imagine that there's a lot there, especially given that it looks like from the press release there might be some secondary things as well. But if we think about Atrium, no, there really isn't a read-through because even the neuromuscular programs at Novartis are continuing to move forward, and therefore there's really no read-through for ours. We're just focused at the moment on getting the Corventis study up and running. Got it. Perhaps let's dive in into the first program. Can you talk about PRKAG2 syndrome in terms of what are the symptoms of patients, how severe those are, how is it diagnosed, and the current treatment and unmet needs? Yeah, sure. PRKAG2 syndrome, it's an autosomal dominant disease. It's a gain of function, which is really the sweet spot for siRNA therapies. Presentation is typically early, in the teens or early 20s, as is often the case with genetic cardiomyopathies. It leads to both an arrhythmogenic cardiomyopathy and also a hypertrophic cardiomyopathy where the heart muscle is thickened. Patients actually have symptoms from both of those. In the background, there's erosion of the conducting system, so they're also getting heart blocks, et cetera, that require pacing. That said, onset of symptoms is typically in the teens or early 20s, but with the arrhythmia side of the disease. Then as the patients get older and the disease continues to progress in the absence of any specific treatments, then they get more and more of the hypertrophic cardiomyopathy symptoms. Also need to bear in mind that there's a relatively high instance of sudden cardiac death in the region of 8%-10% according to the literature. It really is a pretty severe disease. In terms of the underlying cause, G2 or PRKAG2 is the gamma- 2 subunit of AMP kinase, and it's a regulatory subunit. It essentially tells AMP kinase to either switch on and bring lots more glucose into the heart or to switch off and stop bringing in glucose. That's to match the energy uptake of the heart with the energy requirements of the heart. It's basically energy sensing. In the case of the mutations in the gene, the G2 subunit remains permanently switched on, so the heart continues to take up glucose, and that glucose can't be burned off, so it gets deposited within the cardiac myocytes as glycogen. That glycogen is space-occupying and contributes to the hypertrophy. Glycogen acts as an insulator, and it prevents normal conduction through the heart and contributes to the arrhythmias. By knocking down that gamma- 2 subunit, we aim to normalize the AMP kinase activity. Once AMP kinase activity is normalized, then the heart should burn off the glycogen because it just gets converted to glucose and then fed into the energy requirements of the heart and thereby, hopefully, reverse the symptoms of the disease. Got it. Thanks for that overview. I was wondering to follow up on that, can you talk about perhaps, as informed by your preclinical data, how much knockdown is necessary to see a clinical benefit? Yeah, sure. Because we're just looking to normalize activity, we're not looking to completely flatline G2. We're not anticipating that large degrees of knockdown are required. In the animal model, we just tested a single dose, and we didn't do dose ranging, and that single dose caused 75% knockdown. In the animal model with that level of knockdown, we saw that we improved diastolic dysfunction, and we also improved the size of the left atrium in that particular model. The model didn't recapitulate all of the elements of human disease, and it didn't get glycogen accumulation in the heart. That's probably because the mouse heart beats at about 300 beats per second, so they're burning off any excess glucose as quickly as it's coming in. But we did see glycogen uptake in the skeletal muscle, and we were able to clear out that glycogen from skeletal muscle. In humans, we should be able to do that in the heart as well. Got it. So Kath does mention that the potential dosage can be lower when you target the heart compared with the skeletal muscle experience on AOC. Can you comment on the estimated human dose to get to that counterpart for the animal data? Yeah. Within the Corventis clinical trial, we're actually doing flat dosing. At Avidity, we did milligram per kilogram dosing. We saw that the platform was incredibly well-tolerated and also had predictable pharmacology, which has allowed us to move to flat dosing in the Corventis study. That is actually a lot easier for us with drug supply and a lot easier for the sites to manage. The dose range with the flat dosing is 40 mg- 160 mg, and that is equivalent to about 0.5- 2 mg/ kg. So about half of the dose range that we were giving at Avidity. All of those doses based upon our animal work in the rodent and non-human primate should be therapeutic. So what we're looking to do is to test the range of dose response curve as we dose escalate in the Corventis study. Got it. I see. You have this range in mind already. The highest is 2 mg. Yes. The lowest is probably 0.5mg. Yeah. Or that's not- Equivalent to 2 mg/ kg, and in absolute terms, 160 mg of RNA. Okay. Got it. Super helpful. Congrats on the IND clearance for this program. Thank you. Let's talk about the design of this phase I/II, and what do you hope to achieve in this study? Sure. As you said, it's a phase I/II study. It's been designed to be adaptive so that we can react to the data as it comes out. All patients actually receive active drug, so there's no placebo group, and that makes it very easy for us to have eyes on the data in a continuous fashion because we're not unblinding to look at data. It has a phase I part and a phase II part. The phase I part is dose escalation. There we have three different dose escalation cohorts, as I said before, 40 mg, 80 mg, and 160 mg given as a flat dose. We also have an expansion cohort, which is part B of the study, and that's the phase II part. We progress sequentially through the dose escalation up to the maximum dose, then we open up the expansion cohort where additional patients will be treated at the dose that we select for that phase II part of the study. We anticipate that that dose would be the dose that we use for all clinical trial work moving forward, including any registrational cohorts or studies that we do. We are actually looking to have initial proof of concept data from that study in the second half of next year, that will be looking at the pharmacology of the drug in terms of knockdown of the G2 messenger RNA, also tissue uptake, safety, and if there is any other things that we can see, we will look at that as well. One thing that is just important to mention is we know based on prior work with siRNAs that we will get maximum tissue concentration very early within the first couple of doses. We will get maximum knockdown of the RNA very early, again, within a couple of doses. What we do not know is how quickly the intervention with the biology is going to take to changes in glycogen concentration, changes in cardiac structure and function on echocardiography and that kind of thing. We have made the dose escalation portion and the expansion part of the study 48 weeks long to give us a good runway to actually chart out the changes and improvements that we see over a reasonable time course. Patients at the end of that 48 period will get the opportunity to roll over into a long-term extension part that will be focused on long-term safety, and that follow-up there is currently two years, but we would hope to extend that as we go through the development process. Got it. Just quickly on the endpoints. The study as a first-in-human primary endpoint is safety. Secondary endpoints are looking at tissue uptake of the drug and also knockdown of the messenger RNA, and plasma PK. Then the exploratory endpoints are focused on structural and function of the heart, so things like echo, Holter monitoring, ECG, MRI. Then we have clinical endpoints as well, where we're looking at heart failure status, PROs, that kind of thing. Right. Maybe a question on there being no placebo control in the design of the study. I think I remember for the skeletal muscle trials, I think you had controls. In this case, I hear the advantages of getting the study up quickly if it's open label, but is there also other reasons like your confidence of being able to tell placebo effect versus non-actual effect, or based on the endpoint and stuff like that, or some other reasons that made you design it a little differently from skeletal muscle studies? Yeah. For the heart disease, patients don't spontaneously regress in terms of the key parameters that we'll be looking at. So if we're seeing improvements from baseline, they are going to be true improvements. Also, the magnitude of the changes that we're looking for aren't small, whereas a company, our philosophy is to really make a meaningful difference to patients' lives. And so we're looking for large changes, which wouldn't be consistent with a placebo effect. We're also going to be looking very closely at changes on echocardiography in terms of things like wall thickness, left ventricular mass index, cardiac function. All of those deteriorate over time with these patients. There isn't really a spontaneous improvement. Right. Got it. That makes sense. On those efficacy endpoints, I was wondering if you can give us a sense of what are the clinically meaningful changes that we can have in the back of our mind when seeing the data. Yeah. At this stage, really, we're looking for large magnitude changes across the key parameters. Because this is a new novel disease where other therapies haven't been in before, we need to have the conversations with the regulators about what for each of the endpoints that we're seeing constitutes a meaningful change as we power for registrational type studies. That really needs some data out of the Corventis study in order for us to be able to have those conversations. There are some endpoints where other sponsors, for instance, left ventricular mass index, other sponsors have agreed with the agency on changes in the order of 10% to 15% change from baseline. We would hope to be consistent with that, but really each company has to have those conversations individually. Got it. I think, Yanan, all I would add there is our philosophy here in designing the phase I/II is that you actually look at a broad number of endpoints, so we can really gather a fair amount of data, even through the dose escalation portion, to just understand how these different parameters are moving to help inform future study design as well. Right. Got it. I was wondering, is there imaging for the glycogen deposit in the heart? Is that something that will be studied or not really? We will be looking at glycogen deposit, but that will be done on cardiac biopsy. So within the Corventis dose escalation cohorts, we are doing biopsies before treatment and during treatment so that we can have a look at changes in the tissue concentrations and also in cardiac glycogen. There are imaging techniques, but they are not widely done at treatment centers, so it is not something that we can implement study-wide. Got it. You mentioned proof of concept, maybe second half 2027. I was just curious if you see encouraging data in earlier cohorts or the initial patients, is there a possibility that you might share data sooner than the second half of 2027? Brendan, do you want to take that? Yeah, happy to speak to that, Yanan. As Steve mentioned, as we look to proof of concept data, we are looking to show siRNA delivery to the heart, PRKAG mRNA knockdown, as well as safety data. Importantly for us as we think about releasing data, we look to release full cohort data. As all patients in a cohort release progress through their most recent assessment, we will share data at the appropriate times. But we will be sharing safety data up through the data readout for all patients up to that point in time. We will continue to monitor their data as we look to the second half of next year. Great. Let's talk about the size of this population. I think you had initially put out a number, then through your own discussion with labs, you had some updated thoughts. Can you share with us? Yeah, of course. Yes, the number that's out there from a prevalence perspective, we did take from the literature. I think as you take the step back and look at the cardio space as a whole, one figure that really sticks out in my mind is the genetic testing numbers. If you look at it today, there's 2 million people in the U.S. with a cardiomyopathy. About half of those have a genetically driven cardiomyopathy. When you look at that 50% of patients, only about 1% of them today are actually genetically tested. Because of that, when we looked at the literature, it's really difficult to assess how accurate this literature is. We have taken this in terms of this was the number we put out when we first announced these programs back in 2024 with the Avidity team. When we launched Atrium, we wanted to really dig in, and we're really starting early to think about how do we think about this patient population and how do we identify these patients, especially given this challenge on the genetic testing front. What we have done is a number of things. Of course, we're working with the community and talking to the different advocates and to the physicians. Another thing, another tack that we took was to contact some of the labs that are actually doing this genetic testing. What we have found so far from that is that we do believe that that 1 to 2,000 is a very conservative number. The reason for that is just in the first handful of labs that we have contacted, we have identified close to 2,000 individuals with the PRKAG2 gene mutation. That doesn't necessarily mean that those patients have the syndrome. It doesn't mean that they are connected to a physician at this point. That's a pretty large number, especially when you take into context the idea that genetic testing numbers are so low in this indication. When I say that, I mean in genetic cardiomyopathy as a whole. We're continuing to do our work there, but it gives us great confidence that looking at this indication, if you can find that many, and these people are people that had had testing because they likely had some sort of either their family member had the gene or they themselves were having cardiac issues. When you think about that, those numbers might be slightly higher in the PRKAG2 syndrome population, but they're still highly underdiagnosed, just like any other rare disease. We are really looking at this and thinking that we are kind of bringing everybody along for the ride with us in terms of how we are identifying this patient population, because there is not a clear-cut, straight answer on how to get to that. What we are working on right now is really trying to identify what that floor of patients is and think about what does that number truly look like. We are coming to a place where we are feeling like the floor is becoming more clear. It is pretty exciting, actually, to think about this indication, and frankly, the ability to move forward the entire field and start to identify these patients a lot faster through frankly companies like us, but also other companies that are working in the genetic cardiomyopathy space. Got it. That is very interesting to hear. Maybe a quick follow-up. The handful of labs that you looked into, does that represent a big portion or overwhelming majority or only a small portion of all the labs? It does. There is not a ton of labs that do this, so we are really talking about some of the larger labs that we have contacted. Okay. Got it. Yeah. Yeah. Do you think the prevalence will be higher because of how under-tested this condition is, or is it because there are so many other labs that could be doing this, so you are only looking at a small proportion of all the population? Yeah. I think it is more likely to be the first. First It is kind of crazy, Yanan, but through this whole process, I actually have had a family member who has had cardiomyopathy, and to get genetic testing is actually quite difficult. Even as a family member trying to go and ask my physician, I would like to get genetically tested, you got to go through kind of a process. I think what is exciting about this, because I look at that and I think, of course, there could be the downside of that, but the upside of that is that so much is changing right now in the cardio space. We look at ourselves as kind of at the tip of the spear here in terms of making this change in the cardiac space, bringing RNA therapeutics to the heart. There is so much interest in cardiomyopathy itself. It is really the frontier in cardio medicine that has not really been gone after yet, and we are just seeing more and more companies come into this space. We are seeing patient advocates really start to get activated. It feels like we are at this really big turning point, frankly, in the cardio space as well. I think all of those things together, it means that we are kind of rife right now for making a shift in that patient population and really trying to shift the way treatment is being done today. You are hearing it from the KOLs, the community as well. I do think that we are at a place where we are going to start to see that shift, and you will start to see more genetic testing and frankly, more patients just kind of demanding that that is what they want to see. I think that as we go forward, that's a big opportunity, frankly, to partner with other companies in this space and really think about how we do that with the patient communities and the KOLs, too. Got it. Yeah. Thanks for the bigger picture. Let's dive into the second cardiac disease that you are working on, PLN cardiomyopathy. Similarly, can you give an overview of the disease? Then we can talk about the product design side. Yeah, of course. Why don't I start with just kind of a quick overview of the disease, given our time here. Phospholamban is our second program, is ATR 1086. Phospholamban cardiomyopathy or PLN cardiomyopathy is how we refer to it. It is another cardiomyopathy. You tend to see that there's both dilated, arrhythmogenic, and hypertrophic cardiomyopathy for these patients. The most common mutation is the R14del mutation. What that does is it causes protein aggregates, and those aggregates really start to impact cardiac function. This is a disease where you start to see patients have symptoms in their 30s and 40s, prime of their life, as I say right now, given where I am in life as well. Those patients are really suffering. They're getting symptomatic management today. Quite a number of patients actually end up with a heart transplant, which is clearly not a sustainable treatment for these patients. There's no therapies out there for them today, and everything is really symptomatic management. It's really a fantastic opportunity to bring an siRNA for this disease. Got it. Could you talk about how much knockdown is necessary for this condition? Sure. Steve, why don't I pass that to you? Yeah. Again, we don't believe a large amount of knockdown is needed. We've done animal work, but at this point, again, it was with a single dose just to look for signs of efficacy. There, actually in the mouse model, we saw around 75% knockdown, and that 75% knockdown translated into 100% of the mice surviving, whereas all of the untreated mice were dead within a few weeks. Complete maintenance of normal heart function, whereas all of the untreated mice dropped their ejection fraction down to 25%, which is very low. So we saw a profound treatment effect with the 75% knockdown in the mice. But in humans, we really don't believe that we're going to need that level of reduction in order to see clinical effects. Okay. Got it. So the doses used in the animal study for this disease model is higher than the first PRKAG2 model, right? Does that mean the human dose will also be higher here? No, it doesn't. Essentially, when we did the animal studies, we were just choosing a dose to get as much knockdown as we could because the starting place is let's see as much efficacy as we can. The good news is that even with that much higher dose, there were no ill effects from giving the drug. We've also given doses around 3 mg/ kg, which is the same as we did with AG2 in both mice and in non-human primates and saw a very similar level of PLN reduction at the 3 mg/ kg dose as we did at the 6 mg/ kg dose. I think we're just seeing that the knockdown is topping out at the lower doses. Got it. Can you comment on the development timeline for this program? Sure. We are on track. We're hoping to file an IND for this program in 2027. We're moving right along. Got it. Perhaps let's touch on the Bristol Myers Squibb collaboration. I think you received the two milestones very recently and very close to each other. Can you talk about what those milestone payments are for and, just in general, give us a sense of what can we expect next from that collaboration? Sure. Yeah, I'd be happy to. Those two milestones were related to both the development candidate and lead candidate targets related to the collaboration. We're really pleased to have earned $30 million in milestones in our first six months as an independent company. It really continues to be a validation of both the RNA delivery platform and also a form of non-dilutive capital for us. Stepping back, our Bristol Myers Squibb research collaboration is focused in the cardiovascular space and involves up to five targets that can be generated using our RNA delivery platform. Importantly, these targets do not overlap with our wholly-owned precision cardiology pipeline that we're advancing at Atrium. In the Bristol Myers Squibb collaboration, we have the opportunity for up to $2.2 billion in total milestones, and royalties up to the low double digits. Importantly, as we look ahead to future catalysts, as you asked, we typically do not account for future milestones in our cash runway guidance, just given that the timing of if or when we earn those milestones is uncertain. When we've In our cash runway through mid-2028, that does not account for future milestones that we may earn along the way. Got it. To close off, I was wondering, let's talk about, you have two additional indications that you're looking at, right? But you haven't talked about or disclosed what they are. Can you comment on the population size? Sorry, I should have asked this earlier, also comment on PLN cardiomyopathy's population size, and also the next two indications, where it might fall in the size of market. Sure. Why don't we start with PLN? I would take a lot of the same information. A lot of the work we're doing, frankly, for PRKAG2 is kind of a framework for how we will approach PLN as well. It's a very similar situation in terms of under-diagnosis and really working on genetic testing. Again, the literature out there is about 2,000- 4,000 patients with PLN cardiomyopathy. We do anticipate that that will also be a conservative number. We're kind of taking the same approach there. Obviously today we're focused on G2 first, but the PLN work is not far behind. In terms of our next programs, we are quite excited. We do have another program that we are working on a development candidate for. We're anticipating having that next year. We haven't given out a lot of information about that program yet, but I would say, Yanan, as we're thinking about patients and the impact we could have there, we're really looking at expansion in a couple of ways. The first is that we do believe we have indication expansion opportunities for both our PRKAG2 program as well as PLN. Both of them are really central to cardiac function and potentially have the ability to expand and have indication expansion opportunities for each one of those. In addition to that, we have our earlier stage programs. We're going to do everything we can to move these forward. It's an incredible unmet need for these patients, and we're excited to get to do the work. Great. I think with that, we're right on time. Perfect. Thanks so much for the team to share all the insights with us. Thank you, Yanan. Thanks for having us. Thanks, Yanan. Thank you. Great. Thanks everyone.