Morning, everybody, and welcome to day one of the Citizens Life Science Conference. My name is Jon Wolleben, Senior Analyst here. We're pleased to have Astria Therapeutics and CEO Jill Milne joining us today. Astria is a company we launched coverage on, I think, earlier this year in January. We've been covering the hereditary angioedema space for quite some time, and I think this is one of the more compelling pipeline candidates out there. Jill, thanks so much again for joining us. My pleasure. Thanks for having us. You know, I mentioned HAE, but maybe if you could talk a little bit about Astria broadly, your overall strategy and mission. Yeah, for sure. At Astria, our focus is to develop first-choice products for people living with allergic and immunologic diseases. By first choice, we mean that patients and physicians would choose our products first based on the competitive efficacy profile, favorable safety tolerability, and low treatment burden. I think we have that with both of the programs in our pipeline. Our lead program is Navenibart, which we're developing as a preventative therapy for a disease called hereditary angioedema, or HAE. Navenibart is a monoclonal antibody inhibitor of an enzyme called plasma kallikrein. This enzyme is clinically commercially validated for the treatment of hereditary angioedema. What excites us about Navenibart and its potential in HAE is the efficacy profile we've demonstrated in our phase 1b/2 trial with Navenibart that showed a greater than 90% attack rate reduction in patients. That attack rate reduction was with dosing once every three months, and also we showed it with dosing once every six months. A pretty compelling profile that we think will really change the way people live with this disease, hereditary angioedema. Our second program is STAR-0310. That is a monoclonal antibody antagonist of the OX40 receptor. OX40 has become an incredibly interesting pathway. It is a mediator of T cell biology and is implicated in a number of T cell-mediated diseases. It's a mechanism that's been validated in atopic dermatitis. Also, there's been some data this year so far from some of the other programs in the space showing efficacy in diseases in subpopulations in asthma, in HS, and in alopecia. Really interesting mechanism. STAR-0310 for us, we're in a phase 1a healthy subject trial, and we expect to report initial results from that Q3 this year, which we believe will read on the differentiation of STAR-0310 among the OX40 space. There's a lot we like about the story and the strategy. We've got clinically validated targets, known development paths, well-established commercial opportunities, and differentiated profiles. Like, you check those four boxes. There are a lot of buzzwords, but that usually means, you know, you're doing something right, and we're getting rid of a lot of risk out there. When we talk about well-established commercial opportunities, you know, hereditary angioedema is one of the best poster child for rare disease drug development, building a market, finding patients, having good revenues. It's gotten really competitive. Can you talk a little bit about the landscape in the prophylactic setting, how it's changed over the years, you know, what works today? You mentioned Navenibart's, you know, longer dosing. How do you see this fitting in? How does the landscape evolve? Yeah, absolutely. As far as, you know, rare diseases go, hereditary angioedema is pretty unique in that it is a relatively large patient population as far as rare diseases go. You know, as you said, the landscape has evolved incredibly. A little over 20 years ago, there were no mechanism-based therapies for the treatment of HAE. That has changed. What's great is patients now have some options. I think what, you know, what we hope to do with Navenibart is to bring what we think could be a first-choice option to patients. The market itself is large, and it is growing. We anticipate or expect the market to be about $5.4 billion by 2030. That growth is expected to come from earlier diagnosis of patients. Now that there are therapies out there, patients are being diagnosed earlier. We also think greater utilization of preventative therapies is going to expand the market size. Also, geographic expansion. Those three things contribute to the market growth that we expect over the next few years. It is a competitive space, but what gives us confidence in Navenibart to stand out among the other players in the space is, you know, it is based on a trusted mechanism. It is based on a trusted modality. The efficacy profile that we have shown in our phase 1b/2 trial in patients is greater than 90% attack rate reduction, and swelling attacks are the hallmark of this disease, HAE. The fact that the profile that we have built into this program to dose as infrequently as every three months or every six months, depending on the patient needs, we think that really sets Navenibart up to be a highly competitive agent in this space. You know, quite frankly, our vision for it is to become the market-leading product in HAE. Yeah. The other thing that I like is that we've seen evidence of patients' willingness to switch. Some products are sticky in a small percentage of patients, but when something new comes to market, patients are willing to try it because the other thing about the drugs that are out there, and this is true for every drug, it doesn't work for everybody. That's right. When something comes out that may be safer, more tolerable, easier to take, patients are willing to try it in the hereditary angioedema space where patients are well-educated, motivated, and connected. They're pretty well aware of what's going on in development, right? Absolutely. Absolutely. I think, you know, what we've seen in the space is that willingness to switch for things that are better. As the landscape, the competitive landscape and more therapies have come to market, we see patients switching for that better efficacy or better safety tolerability, better, you know, a better fit with their lifestyle. We hope we kind of hit all three of those with Navenibart. You mentioned your phase 1 data earlier, but can you dig into a little bit about what you showed? Sure. Yeah. The phase 1b/2 trial, we read the final results from the original 16 patients in December of last year. What that data showed was that Navenibart over a six-month period, given either once or twice, so that Q3 month or Q6 month dosing, led to a greater than 90% reduction in attack rate, led to a greater than 90% reduction in moderate to severe attacks, led to a greater than 90% reduction in the use of rescue medications, showed a favorable safety tolerability profile, and supported this concept that we have a profile and that could support robust efficacy with very infrequent dosing. How does that compare to what's available today to patients? Yeah. I think it compares quite favorably to what is available today for patients and with what we see coming to the market in the coming months and year in terms of the efficacy profile. The market-leading product is Takhzyro, which is also a monoclonal antibody inhibitor of plasma kallikrein. What we expect for Navenibart is to match or beat Takhzyro in terms of efficacy, to improve upon the tolerability of the injection, and to dose much less frequently. Takhzyro is currently dosed in most patients every two weeks. You can imagine fitting into the lifestyle. If you're traveling, do you want to take a medication that's an injection and have to keep it cold while you're, you know, away for a few weeks? We think Navenibart really will change how people think about living with this disease. Can you talk a little bit about, you know, if we're being critical and we've heard this argument, you've got a small number of patients, you know, open label trial, no control, and you're going right to phase 3. What should give people confidence that the data were for real? Yeah. I think HAE is a pretty unique disease in the sense that these attacks are incredibly objective. Like, a patient has an attack. It's a swelling attack. When a patient swells, you know that they're having an attack. These attacks are adjudicated by the physicians that are overseeing these patients in the trial. That gives us good confidence that what we're seeing is real. Of course, this is a validated mechanism, a validated modality. We have a good indication you inhibit this enzyme, you're going to have a read-through on lowering the attack rate in these patients. We kind of glossed over this, but how are you able to kind of get a longer duration of action for the monoclonal? Yeah. Our antibody was engineered in the FC region. What we introduced was a sequence called YTE. These three amino acid changes lead to an extended half-life of the antibody. That has led, in our phase 1a healthy subject trial, to the half-life being about 90 days for the antibody. It allows for this very infrequent dosing. We're going to get an update from your open label extension, I believe, mid-year. Can you talk a little bit about what data you'll be showing then? Because, you know, when we're talking about smaller patients, when you have more follow-up, that obviously gives us more confidence. What should you guys be showing us in a few months here? Yeah. So, we expect to share data from our AlphaSolar trial. This is the long-term extension from our phase 1b/2 AlphaStar trial. That will be mid-year. What we, you know, that trial was designed, of course, to show long-term safety, but importantly, it also allows us to look at a durability of the efficacy effect in the patients. All of the patients from the AlphaStar, that original 16, chose to enroll in the AlphaSolar. We took that as a good sign that they like what they're seeing in Navenibart for themselves. We'll show efficacy data as well as, again, looking at safety tolerability. Our expectation would be this data would be very much in line with what we showed with the AlphaStar phase 1b/2 trial. Does that mean, you know, 80% attack reduction, or do you want to be in that 90%? Because this is, you know, a threshold disease. If you're mopping up plasma kallikrein, it's hard to have an attack. If you're following people for years, they're going to have a breakthrough attack at some point. How do we think about that balance between, you know, having enough protection, but also, you know, the patients are going to have breakthrough attacks? It happens. Yeah. Great question. Our target profile, as we thought about Navenibart in our design, was to target that 80-90% attack rate reduction. That is what we hope to be able to achieve, not only in this, in the data that we will share with AlphaSolar, the long-term extension, but ultimately what we hope to achieve in the phase three as well. Are you seeing, you know, if someone does have an attack on therapy, is it less severe? Or is there a way to monitor that, like, pre and post-treatment? You know, every attack I used to have, I'd be down for two days versus, oh, now I just have some swelling in my hands. Have you guys looked at severity of attacks on drug? Absolutely. What we've been able to show is that there is a significant reduction in the severity of attacks following treatment with Navenibart. In the phase 1b/2 trial, we showed a greater than, I think it was like a 93%-95% reduction in moderate to severe attacks. Attacks became mild if a patient was going to have them. That's a huge improvement as well. We can reduce attacks by 80%-90% overall, but also the severity of an attack if it should occur. That's, we think, you know, really a game changer for patients. The other, you know, I think really positive development that I'm not sure if people have appreciated quite yet is your phase 3 trial and its design. Can you talk a little bit about, you know, what happened with you guys and FDA and then overview of that trial design? Yeah. We're really thrilled with the design and where we ended up with the design. We're running the phase 3. We're in the single phase 3, we're able to test both the every three-month and the every six-month regimens. That's with a six-month treatment period. The primary endpoint of our pivotal is after six months of dosing. That design enabled us to run a single phase 3 to support both of those dose regimens, which is, I think, great, great for patients and great for us as well. You know, this trial is being run globally, and we expect that this trial should support registration not only in the U.S., but in Europe and Japan as well. We had to align all the regulatory authorities around that design, and we got there. It's a pretty great design, I think, for this program. You know, standard endpoint, right? Percent reduction versus placebo at six months? Yes, at six months. How does that work when you're dosing once? That is the endpoint. Yeah. And just to put that in perspective, the dose for the Q6 month regimen is 600 mg. And that 600 mg dose, when you give it, you get to greater than 80% of steady state right away. And so, that enables you to sort of look at that effect over that six months. But you're right, those patients are getting a single dose. A placebo at three months? Injection at three months? Exactly. Yes. That's right, because it's a single placebo. That's why this is a good trial for patients. I think the regulators saw that as well, you know, to have to run two placebo-controlled trials to support those regimens is not great for patients. We really, great for the regulators to have agreed to that as well. Have you talked about the hierarchy if you're looking at three and six months? You know, which one is your primary and how does that flow through? The way we've done it is the endpoints in the trial are in, they'll be assessed in a hierarchical order as individual arms compared to placebo. That's how it is. There isn't a hierarchy of arms. Each arm is individually compared to placebo. I see. Just given the effect size, that should have enough alpha. Yeah. The alpha, so 0.05 divided by three to cover the three dose arms. This trial was designed to be very well powered, of course, to optimize the chance of success of all three of those arms. Because I can't recall a phase 3 HAE study failing. Yeah. Has it happened? Not that I can recall. It just becomes how do you compare to the other agents either approved or in development? Yeah. And I, yes. And so, we've just seen, you know, obviously Takhzyro was one of the first mechanisms. Well, there were two others before that, but that sort of set the stage, I think, for the efficacy threshold in that 80%-90%. And we just saw Garadacimab and Ionis donidalorsen report theirs in that range as well. We have been covering BioCryst forever. You know, their drug, Orladeyo, once daily oral drug, has seen tremendous uptake. They just raised guidance again. I think that is to our previous comments about patients wanting something more convenient. How do you think about, you know, any leeway you may have in your efficacy or tolerability profile for something that, you know, every six months is such a, you know, paramount difference between every two weeks? Or do you need to have that efficacy profile on par? Like, how do you think about that trade-off? Yeah. I think, so we have good confidence in both the Q3 month and the Q6 month to deliver that 80%-90% efficacy range. I agree with what you're saying. For some patients, you know, maybe the most severe patients or a patient going through a certain point in their life where we know stress induces these attacks, maybe they need to be on a higher dose and might choose our Q3 month option to make sure that they're getting delivered the best dose to meet them where they are in terms of their disease. I think you're right that Orladeyo, I mean, Orladeyo has had a phenomenal launch and, you know, sustained growth for that product. I think that does speak to patients really want something that fits in their lifestyle. For patients on Orladeyo, the equation of, you know, thinking about dosing with an injection every two weeks that's painful, they choose Orladeyo. Do you have any requirements from FDA from a safety perspective about, like, number of doses given because you're dosing so infrequently in your clinical program? Yeah. So, we'll have to have, you know, a safety database as well. The phase three, the way it's designed, we have our pivotal that's that six-month treatment period. All patients will have the ability to choose to go into an extension, a long-term trial following that. It's called our Alpha Expanse. We'll continue to collect data on safety, of course, in that Alpha Expanse. We'll also continue to collect efficacy data as well. All of that together will be part of the submission that ultimately we provide. Will you be able, when will you be able to submit your NDA following the primary endpoint? Will you need longer follow-up or will? That's not critical path right now. Yeah. We haven't given an exact time, but we'll certainly update that as we get enrollment locked down. Yeah. If you guys give guidance for enrollment, you've given a data so we can back out to that. Just, you know, if we have data, what have you guys said, I think first half? Early '27. Early 2027. We back out and then just make sure you're on track for that enrollment. Because it has to be competitive with drugs available and then also multiple clinical programs going on. For sure. You know, I will say we have a pretty exceptional team in terms of clinical operations, clinical development, and our patient advocacy and medical affairs. This is a team that has a whole lot of experience in rare disease phase threes. I think knows what the challenge is and is up for it. We certainly, when we designed the strategy behind the phase three, took into account what other trials would be ongoing at the time. I'll say, to point to the team's exceptional success and excellence in executing, the phase 1b/2 trial rolled in faster than we thought it would. In the U.S. and Canada, we originally thought we were going to have to open sites in Europe to enroll that trial, but enrolled quicker than we can get sites opened up outside of the U.S. That was a good sign. I think the other thing, you know, we designed the phase three for patients. We designed it with input from physicians and patients to make it really as optimal as we could for the patient experience and, quite frankly, the sites and the physician experience as well. All that together is great. I think one thing that we're seeing is a lot of enthusiasm for Navenibart as well. I think the profile of Navenibart is something that has been attractive to patients. That is helping, I think, with enrollment. Maybe last question on Navenibart. Can you talk about the research you've done about potential uptake and the opportunity given, you know, every three- and six-month dosing and how that fits in versus other, you know, options out there? Yeah. So, we've done market research and we've also seen market research done by some other external groups. Including us. Including you, yes. I think it points to that that both the every three-month and the every six-month appear to be real step changes in terms of how people think about treating this disease. You know, I think what we've seen is that market share from our market research and others will come not only from new patients that are just diagnosed with the disease, but also from patients who are currently on a preventative, but are very open to switching to something that fits in their lifestyle better with the efficacy profile that we think we can achieve with Navenibart. We're pretty optimistic about our potential to become that market-leading product in the space. Nevenibart's what caught our attention. And then when we started looking at STAR-0310 as well, also, I think a pretty compelling profile. We think about atopic dermatitis and the size of that market. But, you know, we dug in a little while back. We had phase 3 data for another OX40 agonist that didn't look that great. Why is STAR-0310 going to be different? Yeah. I mean, we're fortunate. This is a, you know, a mechanism in an area where actually learning from the programs ahead of us was really important. When we, so we designed 310 and this program based on learnings from the Amgen program, from the Sanofi program, where we thought taking those learnings and engineering an antibody that we thought addressed the potential liabilities of those programs, we could create something that could be best in class in the OX40 space. I think that's what we have with STAR-0310. What'd you do? As we think about rocatinlimab, we have engineered STAR-0310 to, we hope, avoid the safety tolerability issues associated with T cell killing. Rocatinlimab was an antibody that was engineered to killer T cells. As a result, you see fever and chills as one of the safety tolerability effects in the trials. In a disease like atopic dermatitis, that's just not going to fly. I think what we believed with rocatinlimab is they were going to leave efficacy on the table because they couldn't dose high enough to drive efficacy to levels that you'd want to for a competitive profile in atopic dermatitis. By reducing or eliminating the T cell killing, the ADCC, in STAR-0310, our hope is that we can dose STAR-0310 to levels where we can really drive the efficacy to greater places. Open up that therapeutic window. What's your duration, your target duration for STAR-0310? Yeah. That is another aspect of the program. We also engineered STAR-0310 for a long half-life. It also leverages the YTE half-life extension technology. Our hope with this program is we could dose as infrequently as every six months. That is an important aspect of the OX40 mechanism as well. Not only do we think we can address, you know, the symptoms of atopic dermatitis, but we think this mechanism, based on what we understand about it, we think can be disease modifying in atopic dermatitis. That is one of the real excitements about the space. You mentioned earlier you have a phase one ongoing, data three Q, but healthy volunteers. Are we going to learn enough? What are we going to see? Yeah. So, this phase 1a healthy volunteer trial is pretty important for our program in that we will see if what we engineered in it has really led to what we think could be a differentiated profile that could read on differentiated efficacy, safety, tolerability, and half-life. You know, what we know about the other programs, the rocatinlimab program is in a healthy subject trial, greater than 50% of the subjects in their trial had fever. You know, likely because of the T cell killing. We will be looking very closely at safety, tolerability across our dose range. Half-life will be important for us to establish that we do have an antibody that could be dosed infrequently because we think those two things combined can really lead to our ability to drive efficacy. If we see, you know, a reduced incidence of pyrexia, chills, fever, that should give us some inkling that you're going to have a differentiated profile. It could be really, you know, keep it simple, stupid. If we see that, we're on the right track? Yes. You know, in STAR-0310, we'll also be looking at things like receptor occupancy, knowing we're covering the receptor the way we want to. Yes. So, that's going to be. Counting fevers is easier than triangulating potency to EC50s and EC90s. Okay. Can you remind us in the last little bit of time, your current cash position, you know, runway, including callus that, you know, we talked about, but maybe just putting a button on things to look forward to over the next 12-18 months? Yeah. So, we're in a good, strong cash position, cash into mid-2027. Importantly, through the key milestones for the Navenibart phase 3 program. We'll get through our top line data with that program. That's really important and certainly a priority for the program. Upcoming milestones. We have the Alpha Solar long-term extension data from the Navenibart program that will read out mid-year. That will be data on safety, tolerability, and efficacy of Navenibart following every three-month dosing or every six-month dosing. We have patients who now have been on Navenibart for more than 18 months. We'll have that data mid-year. For STAR-0310, the major milestone is the phase 1a healthy subject data in Q3. Stuff in the next six months even that we'll be looking forward to. Very exciting times. Jill, thanks again for joining us. We'll look forward to catching up with you guys.