Good morning. Thanks for joining our 45th Annual Healthcare Conference. I'm Stacy Ku, part of the Biotech Analyst team with my colleague Vish Shah, and we're happy to be hosting Astria Therapeutics. With us today, we have Jill Milne. Thank you so much, CEO of Astria Therapeutics. Thank you so much for being here today. Obviously, just a short period of time and a lot to cover. In the last couple of months, the team has reported some of, to us, the best-case scenario updates for your lead program, Navenibart, previously STAR-0215, and HAE prophylaxis. Maybe let's take a step back, provide some brief overview of Navenibart, and then recap your recent proof of concept results. We'll drill down. Yeah, for sure. First, thank you for inviting us to participate. Thrilled to be here. I'll take a step back and give a brief overview of Astria. At Astria, we are dedicated to advancing what we call first-choice medicines for patients affected by allergic and immunologic diseases. Our lead program is Navenibart, which is a monoclonal antibody inhibitor of an enzyme called plasma kallikrein that we're developing as a preventative treatment for a disease called hereditary angioedema. Plasma kallikrein, the target of Navenibart, is a clinically and commercially validated target for the preventative treatment of hereditary angioedema, or HAE, as I'll abbreviate it. You're right, we recently reported what we also agree were best-case scenario results from our phase 1b/2 trial in HAE patients with Navenibart, and we reported that earlier than anticipated this past December. Those results support our vision for the profile of Navenibart for the treatment of HAE. Briefly, what we were able to demonstrate with Navenibart in that trial is robust efficacy, a really good safety and tolerability profile, and support for dosing as infrequently as every six months. In that six-month trial, one or two doses of Navenibart led to a greater than 90% reduction in attack rate in patients and up to 67% attack freedom rate, a 95% reduction in moderate to severe attacks, and a greater than 90% reduction in the use of rescue meds. Together, the data we thought was really compelling and supports our vision for Navenibart to become the market-leading product in the preventative treatment of HAE. You talked about the every six-month dosing and how competitive it looks versus some of the other agents out there. I think what's remarkable is that when you look at the every three-month arm and the every six-month arm, the efficacy looks almost the same. I do think that's one aspect of the proof of concept studies. We're kind of keen to see if that reads out in future studies. Again, recent updates, as we look to January this year, you released kind of post-FDA interactions and update for your phase III trial. Can you just walk through what are the different updates, clinical trial design? Yeah, and so certainly, again, I'd say that was a best-case scenario for us as well, because as you know, we originally anticipated running two phase IIIs to support both of those dosing regimens, running a Q3 month first, followed by Q6 month. But based on the regulatory interactions we had, the global interactions, we're thrilled with the final design of the pivotal phase III study, which incorporates both the Q3 month and the Q6 month dosing regimens in a single six-month trial. Again, best-case scenario, and thrilled to have that ongoing now. We just announced last week that that trial is underway. It's been initiated. Exactly. Let's talk about the every three-month and every six-month arm and selection of doses. As we look to the proof of concept, what were the read-throughs and kind of decision-making as you selected doses? Yeah, so we very data-driven selection of doses for that phase III and data-driven from our clinical data to date with Navenibart. What we were aiming for was to advance doses to support the Q3 month and the Q6 month regimens that would produce efficacy that really was best in class as a preventative therapy on par with what Takhzyro, the current market leader, could produce or better. Both dose regimens that support the Q3 and the Q6 month, based on our clinical data to date and our analysis of that data, should provide that level of efficacy that is at or better than Takhzyro. As we think about every six-month dose, we're taking 600 milligrams forward, no loading dose. What are your thoughts there? As it relates to maybe some of the dose selection for phase III, remind us that PK/PD aspect of the proof of concept study is quite important as we think about the different doses and maybe even kind of cohort one, 450 milligram dose, what we saw there as you kind of did a single dose and just tried to see what happens over time for efficacy. A bunch of different questions interlooped there. Just trying to understand the different dose selection for phase III. For sure. You're absolutely right that for that dose selection for phase III, we took into account the PK, the PD, and the efficacy produced in patients that we had seen to date. You're right, from the phase 1b/2 trial, that cohort one data that was produced with 450 milligrams single dose that led to a greater than 90% attack rate reduction in patients through six months of treatment. That was pretty compelling to us. The PK and PD, what that showed us is that we had a very rapid onset of activity and durable activity through six months. Certainly, all of those were taken into consideration as we selected the doses going into the phase III. I think that's one aspect that's pretty compelling about Navenibart, at least as we see it, is this rapid onset of activity. You said no loading dose for the Q6 month, and that's right. That's because that 600 milligram dose gives a very rapid onset of inhibition of plasma kallikrein. Within 24 hours, we're inhibiting plasma kallikrein to levels that we believe are important for driving attack rate reduction. As we talk to our KOLs, they think that the every six month is a total game changer, but they do expect some patients will actually still prefer the every three-month arm. I believe there are two arms for a three-month dosing. Just walk through your decision-making there and what you're trying to achieve in terms of kind of patient flexibility around doses. Yeah, that's one thing that's been very important to us and certainly is built into the design of the phase III is that concept of offering flexible dosing for patients and physicians. We agree that the Q6 month is a game changer, but equally so from what we've heard from patients and physicians, that Q3 month is as well, that some patients are just going to feel more comfortable with an every three-month dosing regimen. We want to be able to provide both of those dosing regimens to patients so that they can select what works best for them. Did I answer the whole? Yeah, as we think about the two different Q3 arm doses, selection of kind of maybe the higher, I think it's one arm is going to be a lower dose, the second arm is going to be a higher dose. That's right. In our phase III, we have three Navenibart arms for the adult patients. The first one is a Q3 month. It's a 600 mg dose followed by 300 milligrams every three months. The second arm is the six-month, it's 600 milligrams every six months. There is a third arm that's 600 milligrams every three months. We believe that those first two cohorts, the first two dose regimens, are going to cover the majority of patients sufficiently. That's going to put them at the Takhzyro plus efficacy level. That third dose, the 600 milligrams every three months, is for patients that may need a higher dose for a number of reasons or may feel more comfortable at the highest dose possible. That's why that was incorporated. To give that flexibility to the patient and the physician to choose what works best for the patient. I understand that we're spending a ton of time on the phase III design, but I do think it was really thoughtfully designed. As we think about patient flexibility, we also have a unique open label extension trial. Maybe talk about part one, part two, what are you trying to achieve in kind of each aspect? Yeah, and I certainly will give a shout out to Chris, our CMO, and our clinical team for the innovative design of the phase III program for Navenibart. We are incredibly thrilled with the design we've ended up with and that long-term extension for the phase III called Orbit Expansion. You are right, that has two parts, which I think are incredibly interesting and hopefully going to really support what we hope to achieve with patients in HAE with Navenibart. Part one of that extension trial, patients from ALPHA ORBIT phase III have the opportunity to move into that extension. In part one, which is six months in duration, they'll go on to the same dose of Navenibart that they were on in the phase III. The placebos will go to the highest dose, so that's 600 milligrams every three months. That's part one. We'll continue to collect efficacy data, safety, tolerability data. Part two is where it becomes interesting. At part two, after six months in part one, they move on to part two where the patient and physician choose which regimen they think will work best for them going forward with their particular lifestyle and disease. That's where the dosing flexibility is introduced. That will go on for another six months or longer, as long as the patients want to stay on. Remind us, when are we going to get data? And then from there, when would your expected NDA filing be based on the safety data that we're grabbing from the open label extension? Sure. We are anticipating having top-line data from the phase III trial in early 2027. Of course, we're going to do everything in our power to work as efficiently as possible to execute upon this trial. We'll see if we can beat those, exceed those timelines. In terms of the long-term extension, that data is not critical path to a filing, really. It's the top-line data from the pivotal phase III, the ALPHA ORBIT trial. Certainly, the long-term extension data will be incorporated into registration filings for Navenibart and will be an important component of that, but won't be rate limiting as we've laid out the plan to date. Okay, it would be helpful for the label, but you could always add it on as data progresses. Yes, it'll be certainly important for the label to collect more efficacy data and more safety data. Based on our projections of enrollment, won't be rate limiting. At the beginning, you did mention plasma kallikrein inhibitor, high familiarity given Takhzyro's mechanism of action, very, very similar type of, let's say, target. Not the same, but very similar. What do you think about enrollment? I know it's very, very early days, but are you seeing a lot of excitement from kind of investigators? Are you seeing patients very willing to try something that they already know? Yeah, I think that's a huge advantage for Navenibart. It's a trusted mechanism already, plasma kallikrein inhibition, and a trusted modality, a monoclonal antibody. It's very much like the market-leading product. A very easy conversation to have with patients and physicians. I think that certainly plays to our favor. We've heard a lot of excitement and interest from both patients and physicians who are participating in the trial. Do you expect similar level of ease to enroll both adults and adolescents? I think we have 135 adults that we anticipate enrolling in the trial and 10 adolescents. Certainly a different order of magnitude. I think there is a lot of interest. I could imagine from an adolescent perspective, being on a drug that's dosed as infrequently as Navenibart could be a really attractive proposition for young patients. Understood. As the phase III progresses, we are going to get additional information from the phase II B aspect of your proof of concept study. Maybe to the extent that you can, number of patients that you might disclose from the ongoing open label extension trial, the redosing, how many redosing, I guess, doses will you get? What kind of efficacy should we expect? Yeah, so that's our long-term extension trial from our phase 1b/2, which is called Alpha Solar. We anticipate sharing an interim read from that middle of this year. What that will include is long-term data from patients who've been in the Alpha Star phase 1b/2 and opted to go in. I should point out that all patients who've been in that phase 1b/2 trial have opted to go into Alpha Solar. I think that's a vote of confidence for the profile. We'll have patients and we'll report data for patients who've been dosing for 12 to 18 months on Navenibart. In that Alpha Solar data set, we'll have patients who've been on the Q3 month, 300 milligrams Q3 month, and patients who've been on the 600 milligram Q6 month. That'll be nice data to take a look at to look at durability of the efficacy and also, of course, safety tolerability as well. Are you expecting similar level of efficacy as what we saw in the proof of concept? That's certainly the expectation. I think it's certainly a vote of confidence from patients and physicians to have all of the patients who were in the Alpha Star trial opt to go into that and stay in it. I think that's a good sign. I guess we're expecting around 15 maybe plus patients then. Is that a fair estimate? We had in the original set in Alpha Star, there were 16 patients who enrolled, yes. Perfect. Wonderful. As a reminder, I believe the efficacy hurdle that you've discussed in the past is 80-90% reduction of DAX. That's right. Wonderful. As we think about the HAE prophylaxis competitive landscape, there are obviously multiple agents that are in development. Obviously, to us, the KOLs tell us that every three months and every six months should lead to meaningful adoption versus maybe every one month dose. Maybe talk about your market research, what the KOL feedback has been so far to your proof of concept results, and how do you think those two different treatment frequencies will be used? Three months versus six months because you've done a lot of that work. Yeah, so we've done market research both in patients and in physicians. Most recently, we did a market research study in 50 treating physicians from the United States. I'd say what we tested was a product with a profile like Navenibart that was offered as both a Q3 month and a Q6 month regimen. We asked how that would be utilized in their practice. I think we were thrilled with the responses. Those 50 physicians said that they would use Navenibart in 53% of their patients who were newly diagnosed and in 46% of their patient population that was already on a preventative therapy. That was pretty compelling to us that perhaps we could be looking at a market share in the 50% range, which we agree with the potential of Navenibart and the excitement around it based on the profile we've generated clinically to date and what we think it can offer for patients. Understood. In the discussions you've had with KOLs, HAEGARDA still remains a fairly sticky market, but it's twice a week dosing, and it's pretty onerous. What are they saying for these patients? What's really going to kind of shake these patients up from switching? Yeah, I think the market has really changed. If you think about the HAE market, 15 years ago or so, there were no mechanism-based therapies. I think patients who all of a sudden had a HAEGARDA or a CINRYZE, it was, I'm not going to change anything because I finally have something that is controlling my disease. I think that's changing. I think a good example of why we think the market is not as sticky as everyone talks about is look at the success of Orladeyo, which had half the phase III efficacy from Takhzyro but has certainly had a lot of uptake in the market because I think it offered something that Takhzyro couldn't offer to patients, a much more patient-friendly approach. We're pretty optimistic. From the market research we've done both with patients and physicians, the market isn't as sticky as I think we all believed. That's fair, especially as we think about kind of other recent entrants in the market. Last question on competitive landscape. There obviously are maybe some ways away, but there's always going to be kind of new investor fears of longer-acting agents. Maybe talk about gene therapy approaches with Intellia's NTLA-2002. I don't know if anyone else pronounces it that way. Maybe ADRX's HAE approach. Yeah, I think those are coming in the future as well. I think Navenibart has something that's pretty unique and special among all of the therapies that are either on the market or in development. It's a trusted mechanism. It's a trusted modality in the form of monoclonal antibody. That gives a lot of comfort to patients and physicians. Also, the efficacy profile we've generated to date with Navenibart shows that it has efficacy on par, if not better, than the market-leading product, Takhzyro. Also, as we look at the Intellia's and the potential of NTLA-2002, safety tolerability profile with Navenibart has been clean. I think this modality has been associated with a very clean safety profile as well. In addition, the time to onset of efficacy, I think, is going to be something that continues to be important for patients. There is a much faster onset with a product like Navenibart and what we have been able to demonstrate already compared to those products as well. I think altogether, and also the concept for us of the YTE modification of the antibody to allow this very infrequent dosing as infrequently as every six months makes a pretty compelling case when you put all that together for Navenibart having the potential to be the market-leading product. Understood. Six months seems to be a bit of a sweet spot. I think once you get 12 months and you think about the patient population, there may be some hesitation, especially as we think about patients that clearly are telling their clinicians that they would want three-month dose. That's right. You mentioned the YTE technology. We do want to make sure we cover that distinction versus Takhzyro. This is an entirely different binding site to our best understanding. Just maybe a quick reminder on the patents that are filed and what type of exclusivity you might expect. Yeah, so it's definitely a different antibody than Takhzyro. It incorporates that YTE as well as different sequences that we've filed for composition of matter IP, which, if granted, would provide coverage out through 2042. We also have filed for dosing patent coverage as well. If granted, would cover us through 2043. A nice length of time left on our potential patent estate. Wonderful. We do want to make sure we spend some time on your second asset, STAR-310. Maybe briefly talk about the distinctions between your asset, Rocatinlimab, and Amlitelimab.. Yeah, STAR-310 is a monoclonal antibody antagonist of the OX40 receptor. More like Rocatinlimab from that perspective of mechanism. I will start by saying this is a place where we have incorporated the learnings from both the Amlitelimab. program and the Rocatinlimab program in our STAR-310 program. I think we've greatly benefited from the work that they've all laid out ahead of us. Both antagonists or antibodies against the ligand and the receptor have shown good efficacy in phase II in atopic dermatitis. For us, we think that the receptor is the way to go because the receptor is only expressed on activated T cells. It's the activated T cell that you want to target in diseases like atopic dermatitis or other T cell mediated diseases, and hence how we got there. What we chose to do was to design an antibody that we thought would have high potency, high affinity for the receptor, competitive efficacy, and good safety and tolerability and low treatment burden. Again, we've introduced the YTE to allow for infrequent dosing. Different than Rocatinlimab, which also targets the receptor, Rocatinlimab was engineered to have high ADCC, so to kill T cells. What that appears to have led to is a high rate of AEs in their trial, so fever and chills that are typically associated with ADCC-like activity. I think what that has done is limit the therapeutic window under which they can operate. We took that learning into our program and have dramatically reduced ADCC in our approach. The idea being that we can open up that therapeutic window, go to doses without the potential for that ADCC-like fever chills effects and really drive efficacy. Within atopic dermatitis, I think it's interesting. The hurdle is obviously post-tapillamab, but what gets KOLs most excited is the infrequency of treatment. I do think the YTE technology should be an interesting thing to look out for. Unfortunately or not, the value for 310 has been entirely washed out, I would say, of the valuation. With that in mind, maybe talk about Rocatinlimab, the phase III data, what I guess publicly disclosed information that we have that might be unfairly attributed to kind of the class. Yeah, so Rocatinlimab reported their first phase III readout late last year. That was disappointing efficacy in comparison to what they reported at phase II B. It still showed efficacy in atopic dermatitis that was statistically significant, they hit their endpoints, but it was just less than what they saw in the phase II B. There's still a lot to learn from that phase III that they reported on. They've yet to report the dose that was used in that trial, the characteristics of the patient population, and also details of the safety tolerability. One hypothesis that's been floated is that they lowered the dose going into phase III to try to get around the fever chills, AEs that have been associated with that program to try to have a better profile. That could have led to lower efficacy. It's also possible that, in addition to a different patient population, led to a different inefficacy. I think we felt that a little bit, people confusing people about the potential of targeting the receptor. Understood. I do believe they did disclose that they essentially extended the dosing frequency from every two weeks to every four weeks. You covered all the other aspects. Yep, that's exactly right. Understood. As a reminder to the audience, we are getting a lot of competitive read-through to the OX40 class this year. We are going to get Sanofi's Amlitelimab., at least asthma and hidradenitis suppurativa results, proof of concept results in the first half, and potentially atopic dermatitis results by year-end. There are a number of different indications. You all have started your phase I in healthy volunteers in January, and we could get potential results in Q3. What kind of disclosures could we expect in healthy volunteers that would help us have read-through to atopic dermatitis? Again, as we are getting all of these different other potential indications where OX40 could be useful or could be pursued, how quickly could you move into some of these other indications? Yeah, I'll start with the phase I a and the Q3 data that we intend to share. That phase I a will be important for us in looking at the potential profile of STAR-310 and also helping us select doses to go into the first patient trial. What we'll clearly be looking at is certainly safety, tolerability, and looking for differentiation from programs like Rocatinlimab in that aspect. Also looking at PK for sure to demonstrate that we can support a less frequent dosing regimen. We'll use all of that information to help us select doses that we believe will produce robust efficacy in patients. When we started to get interested in the OX40 mechanism, it was because of the broad potential in diseases like atopic dermatitis, but in a broad range of other T cell mediated diseases. We internally have been looking at potential opportunities for the OX40 mechanism in other diseases. We are very eager to see the outcomes of this Sanofi data in HS and asthma in the first half of this year. I think that will be compelling. I think in atopic dermatitis, just to make the distinction from Dupixent, this mechanism, OX40, has the potential to have a broader effect than just a TH2 mediated mechanism like dupilumab. I think that is why there is so much excitement in it to have that broader potential to hopefully reach a broader set of patients. Yeah, and it's interesting when we talk to KOLs, obviously they're very comfortable with using kind of JAK inhibitors, which is not necessarily the case for most dermatologists treating atopic dermatitis. We do think that there's green fields in between the two, but unfortunately, JAK inhibitors do influence efficacy expectations. We will have to see how all the different agents stack up among KOLs, but also among kind of the community treating dermatologists. In the last few moments, maybe just I know we hopped around all the different catalysts, but just remind us for this year and maybe the beginning of next year, what's the catalyst pathway for you all? Yeah, so 2025 is going to be an exciting year, and we're off to an amazing start. I'll start with the Navenibart program. An important milestone this year was to initiate the phase III trial with Navenibart. Of course, we announced that last week that that is now up and running and ongoing. For Navenibart, we also anticipate releasing Alpha Solar long-term extension data, which we hope will show a read on durability of the efficacy of Navenibart in patients on a Q3 month and a Q6 month regimen. That'll be mid-year. For the STAR-0310 program, we're off to a fast start there as well. We initiated the phase I A trial earlier this month. That trial is ongoing and on track to allow us to deliver interim results in Q3, which will be important for assessing the potential and selecting doses for the first patient trial. Wonderful. To us, sounds like a catalyst-rich next six to twelve months. In the last few moments before we end, this is obviously a unique scenario where the KOL feedback could not be more overwhelmingly effusive. No investor debates the likelihood of Navenibart's success or the ability to reach a billion dollars in peak sales, but the stock is trading close to, last we looked, $50 million EV. We get a lot of inbounds on HAE, and this is one that we think is underappreciated. If there's any last comments you'd like to make about kind of our open-ended discussion, appreciate it. Yeah, I mean, we also agree, underappreciated. I think high potential for success with Navenibart and based on the profile we've been able to support clinically, I think is there. I think having the phase III clarity, we hope will turn the tables on how people view this program, that now we have a trial design and a single pivotal phase III that can support both that Q3 and Q6 month regimen. I think the macro environment's been a little crazy. For us, it's getting out there and explaining the potential of Navenibart and continuing to execute as we have been. Okay, wonderful. Thank you so much for your time. Really, really appreciate it. Thank you. Thank you.