Atrium Therapeutics, Inc. (RNA) September 2026 Conference Transcript

Okay, great. Thanks, everyone, for being here, and welcome to the Wells Fargo Healthcare Conference. My name is Yanen Zhu. I'm one of the biotech analysts here. It's my great pleasure to be joined by the management team of Atrium Therapeutics. With me here today are Cass Gallagher, President and CEO, Brandon Winslow, CFO, and Steve Hughes, CMO. Thank you for being here.

Good morning, Yan. And thank you so much for having us. It's really nice to be back. Great to see you.

Yeah, great to be hosting the team. So I was wondering, Cassie, if you can start us off with an overview of the company and its formation.

Yeah, of course, of course. So I'll get started, and then maybe, Brendan, I'll hand it over to you to talk a little bit about the formation. So, Atrium, we just passed our six-month mark. So 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. And it's 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're able to work on. And so the first two, we have our first one for PRK-AG2 syndrome, which is going to be entering the clinic shortly here. We're in the final processes of just getting our phase one up and running to initiate our first patient. We have a second program in phospholamine cardiomyopathy. And beyond that, we have two additional programs also for genetic cardiomyopathies. You know, 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, and most of those patients today are treated with symptomatic management. And so 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. And you mentioned Brandon. We'll talk about that.

Yes, I'm sorry.

Yeah, happy to. So, Yana, as you think about the impetus for the spin-out transaction with Atrium, you'll recall that Avidity's portfolio consisted of both late-stage neuromuscular assets as well as earlier-stage precision cardio programs. And 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 PRKG2 syndrome and PLN cardiomyopathy, these are diseases that have no approved therapies for their underlying cause of their diseases. And we're going to be paving new pathways along the way, which as a smaller biotech, we're particularly well-suited for. Got it, 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. you?

Absolutely. So when you think about AOCs, what we are doing with them is we're using a monoclonal antibody to the transferrin receptor. And then what we are doing is linking that to an siRNA. And 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. And so the AOC platform really allows us to deliver, for example, an siRNA to PRK-AG2 to the heart. Now, AOCs in particular and the transferrin receptor, we really get a tremendous amount of, there's a lot of transferrin receptor in the heart. And so because of that, our AOCs really have a lot of delivery there. You'll even see, you know, as we talk later about our dosing in our phase one, two study that we have to, we don't have to use as high of doses, things like that because of the fact that we get so much more into the heart. And so it really is this kind of twofold piece of the heart itself really, you know, it really has a lot of transfer and it's naturally expressing it. So we're utilizing that natural biology to get in there. And 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, great. That's great to hear. I was wondering if you can also touch on the news from last night from the DM1 study, whether that has any read-through to a cardiovascular or cardiac muscle-targeted approach.

Yeah, so, you know, let me answer your question by saying no, it does not have any read-through to atrium. you know, 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, you know, even the neuromuscular programs at, you know, 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 Coventus study up and running.

Got it. Got it. Let's perhaps let's dive in into the first program. Can you talk about PRK-AG2 syndrome in terms of what are the symptoms of patients, how severe those are, how is it diagnosed, and the current treatment, and are my needs?

Yeah, sure. So PRK-AG2 syndrome, it's an autosomal dominant disease. It's a gain of function, which is really the sweet spot for SI-RNA therapies. And presentation is typically early in the teens or early 20s, as is often the case with genetic cardiomyopathies. It leads to both an arrhythmic cardiomyopathy and also a hypertrophic cardiomyopathy where the heart muscle is thickened. So patients actually have symptoms from both of those. And in the background there's erosion of the conducting system so they're also getting heart blocks etc that require pacing. That said, onset of symptoms is typically in the teens or early 20s but with the arrhythmia side of the disease and 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. I also need to bear in mind that there's a relatively high incidence of sudden cardiac death in the region of 8% to 10% according to the literature. So it really is a pretty severe disease. In terms of the underlying cause, G2 or PLKG2 is the gamma-2 subunit of AMP kinase, and it's a regulatory subunit. So 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, and that's to match the energy uptake of the heart with the energy requirements of the heart so 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 as glycogen and that glycogen is space occupying and contributes to the hypertrophy but also glycogen acts as an insulator and it prevents normal conduction through the heart and contributes to the arrhythmias. So by knocking down that gamma 2 subunit, we aim to normalize the AMP kinase activity and 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 pre-clinical data, how much knockdown is necessary to see a clinical benefit?

Yeah, sure. So 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 and 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 muscles so in humans, we should be able to do that in the heart as well.

Got it, got it. So Cass does mention that the potential doses 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, you know, counterpart for the animal data?

Yeah, within the Corventis clinical trial, we're actually doing flat dosing so 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 Corventus study and 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 mgs to 160 mgs and that is equivalent to about 0.5 to 2 mg per gig. 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. And so what we're looking to do is to test the range of the dose response curve as we dose escalate in the Corventus study.

Got it. Got it. I see. So you have this range in mind already. So the highest is 2 mg. Lowest is probably 0.5.

Yeah, equivalent to two mgs per kg, and in absolute terms, 160 milligrams of RNA. Okay, got it, super helpful.

Maybe, so congrats on the IND clearance for this program. Let's talk about the design of this phase one, two, and what do you hope to achieve in this study?

Sure. So as you said, it's a phase one, two study. It's been designed to be adaptive so that we can react to the data as it comes out. And all patients actually receive active drugs, 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 one part and a phase two part. The phase one part is dose escalation so there we have three different dose escalation cohorts as I said before 40 80 and 160 milligrams given as a flat dose and we also have an expansion cohort which is part B of the study and that's the phase two part so we progress sequentially through the dose escalation up to the maximum dose and then we open up the expansion cohort where additional patients will be treated at the dose that we select for that phase two part of the study and we anticipate that that dose would be the dose that we use for all clinical trial work moving forward including any registration or cohorts or studies that we do. We're actually looking to have initial proof of concept data from that study in the second half of next year and 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's any other things that we can see we'll look at that as well. One thing that's just important to mention is we know based on prior work with siRNAs that we'll get maximum tissue concentration very early within the first couple of doses. We'll get maximum knockdown of the RNA very early, again within a couple of doses, what we don't 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. So we've 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 that 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. So just quickly on the endpoints that 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. And then the exploratory endpoints are focused on structure and function of the heart, so things like echo, halter monitoring, ECG, MRI, and then we have clinical endpoints as well where we're looking at heart failure status, PROs, that kind of thing.

Right, right, right. So 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 some based on the endpoint and stuff like that or some other reasons that made you, you know, make the design a little differently from the 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. As 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. That makes sense. On those efficacy endpoints, I'm wondering if you can give us a sense of what are the meaningful, 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. regulators. 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 registration type studies. And that really needs some data out of the Corventus study in order for us to be able to have those conversations. There are some endpoints where other sponsors, so for instance, left ventricular mass index, other sponsors have agreed with the agency on changes in the order of 10 to 15 percent change from baseline. We would hope to be consistent with that, but really each company has to have those conversations individually. Carl, Carl.

I think Jan and all I would add there is, you know, our philosophy here in designing the phase one, two, is that you actually look at a broad number of endpoints. And 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. 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 Corventus dose escalation cohorts, we're 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're not widely done at treatment centers so it's not something that we can implement study-wide. Got it, got it.

So 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 second half, 2027?

Yeah, happy to speak to that, Yanin. So as Steve mentioned, as we look to proof of concept data, we're looking to show siRNA delivery to the heart, PRKG mRNA knockdown, as well as safety data. Importantly for us as we think about releasing data, we look to release full cohort data. So as all patients in the cohort really progress through their most recent assessment, we'll 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. And so we'll continue to monitor their data as we look to the second half of next year. Great, great.

Let's talk about the size of this population. I think you had initially put out a number and then through your own discussion with labs, you had some updated thoughts. Can you share with us?

Yeah, of course. So, yes, the number that's out there from a prevalence perspective, you know, we did take from the literature. And I think as you're, you know, as you kind of take the step back and look at the cardio space as a whole, you know, one figure that really sticks out in my mind is the genetic testing numbers. So if you look at it today, there's 2 million people in the United States with a cardiomyopathy. About half of those have a genetically driven cardiomyopathy. And then when you look at that 50% of patients, only about 1% of them today are actually genetically tested. And so because of that, you know, when we looked at the literature, it's really difficult to assess, you know, how accurate this literature is. We have taken this in terms of, you know, this was the number we put out when we first announced these programs back in 2024 with the Avidity team. But when we launched Atrium, we wanted to really dig in, and we're really starting early to think about, you know, how do we think about this patient population, and how do we identify these patients, especially given this challenge on the genetic testing front? So 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. But another thing, another tact 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 PRK-AG2 gene mutation. So that doesn't necessarily mean, you know, that those patients have the syndrome. It doesn't mean that they are connected to a physician at this point, but that's a pretty large number, especially when you take into context the idea that genetic testing numbers are so low in this indication. And when I say that, I mean like in genetic cardiomyopathy as a whole. And so, you know, we're continuing to do our work there, but it gives us great confidence that, you know, looking at this indication, if you can find that many and, you know, 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. So when you think about that, you know, those numbers might be slightly higher in the PRK-AG2 syndrome population, but they're still highly underdiagnosed, just like any other rare disease. And so we're really looking at this and thinking that we are kind of bringing everybody along for the ride with us in terms of how we're identifying this patient population, because there isn't a clear-cut, straight answer on how to get to that. But what we're 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're coming to a place where we're feeling like the floor is becoming more clear. And it's, you know, 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, you know, through, you know, frankly, companies like us, but also other companies that are working in the genetic cardiomyopathy space.

Got it. That's 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. I mean, there's not a ton of labs that do this, so we're really talking about some of the larger labs that we have contacted.

Okay, got it.

Yeah.

Yeah. But you do think there are, 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's more likely to be the first, which is that there's just, you know, it's kind of crazy, but through this whole process, I actually had a family member who's had cardiomyopathy. And to get genetic testing is actually quite difficult. So even as a family member trying to go and ask my physician, I'd like to get genetically tested, you kind of go through kind of a process. And so I think that what's exciting about this, because I look at that and I think, you know, 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. You know, 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. But, you know, there's so much interest in really this in cardiomyopathy itself. It's really the frontier in cardiomedicine that has not really been gone after yet. And we're just seeing more and more companies come into the space. We're seeing patient advocates really start to get activated. So it feels like we're at this really big turning point, frankly, in the cardio space as well. And I think all of those things together, it means that we're 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're hearing it from the KOLs, the community as well. And so I do think that we are at a place where we're 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. And I think that as we go forward, that's a big opportunity, frankly, too, 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. Got it. Yeah. Thanks for the bigger picture. But let's dive into the second cardiac disease that you are working on, PLN cardiomyopsy. Similarly, can you give an overview of the disease? And then we can talk about the product design side.

Why don't I start with just kind of a quick overview of the disease, given our time here. So phospholamine is our second program, is ATR1086. Phospholamine 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. It's caused by the most common mutation is the R14-Dell mutation. And what that does is it causes protein aggregates. And those aggregates really start to impact cardiac function. So this is a disease where you start to see patients have symptoms in their 30s and 40s, you know, prime of their life, as I say right now, given where I am in life as well. And so, you know, 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. So without any, 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, got it. Could you talk about how much knockdown is necessary for this condition?

Sure. Steve, want to pass this?

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 and they're actually in the mouse model we saw around 75% knockdown and that 75% knockdown translated into a hundred percent 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 it which is very low. So we saw 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, got it. So the doses used in the animal study for this disease model is higher than the first PRK AG2 model, right? Does that mean the human dose will also be higher here?

No it doesn't. So essentially when 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 we even with that much higher dose that there were no ill effects from giving the drug but we've also given doses around 3 mg per kg which is the same as we did with AG2 in both mice and in non-human primates and saw very similar level sort of PLM reduction at the 3 milligram per kilogram dose as we did at the 6 milligram per kilogram dose. So I think we're just seeing that the knockdown is topping out at the lower doses.

Got it. Got it. And can you comment on the development timeline for this program?

Sure. So we are on track. We're hoping to file an IND for this program in 2027.

So we're moving right along got it got it got it um perhaps let's uh touch on the bms uh collaboration i think you received the two milestones very recently and uh very close to each other can you talk about what that those milestone payments are for and uh just in general give us a sense of what other what can we expect next from that collaboration yeah i'd be happy to So, 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 BMS 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 cardio pipeline that we're advancing at Atrium. In the BMS 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. And in our cash runway through mid-2028, that does not account for future milestones that we may earn along the way. Got it, 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? And sorry, I should have asked this earlier. Also comment on PLN, cardiomyopsy's population size, and also the next two indications where it might fall in the size of market.

Sure, sure. So why don't we start with PLN? So 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 underdiagnosis and really working on genetic testing. So again, the literature out there is about 2,000 to 4,000 patients with PLN cardiomyopathy. We do anticipate that that will also be a conservative number. And so, you know, 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, Yen, and as we're thinking about patients and the impact we could have there, we're really looking at expansion in a couple of ways. So the first is that we do believe we have indication expansion opportunities for both our PRK-AG2 program as well as PLN. Both of them are, you know, really central to cardiac function and potentially have the ability to expand and have indication expansion opportunities for each one of those. And in addition to that, we have our earlier stage programs, and 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, great. I think with that, we're right on time. Thanks so much for the team to share all these insights with us.

Thank you, Yan, and thanks for having us.

Thank you. Thanks, everyone.