Astria Therapeutics, Inc. (ATXS) Earnings Call Transcript & Summary

Good morning, everybody, and welcome to day 1 of The Citizens Life Science Conference. My name is John 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. So Jill, thanks so much again for joining us.

My pleasure. Thanks for having us.

And I mentioned HAE, but maybe if you could talk a little bit about Astria broadly, your overall strategy and mission.

Yes, for sure. So at Astria, our focus is to develop first choice products for people living with allergic and immunologic diseases. And -- 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. And I think we have that with both of the programs in our pipeline. So 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. And 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 Ib/II trial with Navenibart that showed a greater than 90% attack rate reduction in patients. And that attack rate reduction was with dosing once every 3 months. And also, we showed it with dosing once every 6 months. So a pretty compelling profile that we think will be -- 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. And 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. So really interesting mechanism. So STAR-0310 for us, we're in a Phase Ia 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 got clinically validated targets, known development paths, well-established commercial opportunities and differentiated profiles. Like you check those 4 boxes, there are a lot of buzzwords, but that usually means you're doing something right, and we're getting rid of a lot of risk out there. But when we talk about well-established commercial opportunities, hereditary angioedema is one of the best poster trials 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? What works today? And then you mentioned Navenibart's longer dosing. But how do you see this fitting in? How does the landscape evolve?

Yes, absolutely. So as far as rare diseases go, hereditary angioedema is pretty unique in that it is a relatively large patient population as far as rare diseases go. And 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. And what's great is patients now have some options. And I think what we hope to do with Navenibart is to bring what we think could be a first choice option to patients. But the market itself is large, and it is growing. It's -- 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 and then also geographic expansion. So those 3 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 it's based on a trusted mechanism. It's based on a trusted modality. The efficacy profile that we've shown in our Phase Ib/II trial in patients, this greater than 90% attack rate reduction in swelling attacks are the hallmark of this disease, HAE, and the fact that the profile that we've built into this program to dose as infrequently as every 3 months or every 6 months, depending on the patient needs, we think that really sets Navenibart up to be a highly competitive agent in this space. And quite frankly, our vision for it is to become the market-leading product in HAE.

And 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. So 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 development, right?

Absolutely, absolutely. And I think what we've seen in the space is that willingness to switch for things that are better. And 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, a better fit with their lifestyle. And we hope we kind of hit all 3 of those with Navenibart.

And you mentioned your Phase I data earlier, but can you dig into a little bit about what you showed?

Sure. Yes. So the Phase Ib/II trial, we read the final results from the original 16 patients in December of last year. And what that data showed was that Navenibart over a 6-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?

Yes. So 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. So 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 2 weeks. And 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 away for a few weeks. So we think Navenibart really will change how people think about living with this disease.

And can you talk a little bit about if we're -- be critical and this -- we've heard this argument, you got a small number of patients, open-label trial, no control and you're going right to Phase III. What should give people confidence that the data were for real?

Yes. 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. And these attacks are adjudicated by the physicians that are overseeing these patients in the trial. And so that gives us good confidence that what we're seeing is real. And of course, this is a validated mechanism, validated modality. So 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.

And we kind of glossed over this, but how are you able to kind of get a longer duration of action for the monoclonal?

Yes. So our antibody was engineered in the Fc region. What we introduced was a sequence called YTE, so these 3 amino acid changes that lead to an extended half-life of the antibody. And that has led in our Phase Ia healthy subject trial, the half-life was about 90 days for the antibody. So it allows for this very infrequent dosing.

And we're going to get an update from your open-label extension, I believe, midyear. Can you talk a little bit about what data you'll be showing then? Because we're talking about small number of patients when we have more follow-up, that obviously gives us more confidence. But what should you guys be showing us in a few months here?

Yes. So we expect to share data from our ALPHA-SOLAR trial. This is the long-term extension from our Phase Ib/II ALPHA-STAR trial. And so that will be midyear. What we -- that trial was designed, of course, to show long-term safety, but importantly, it also allows us to look at durability of the efficacy effect. In the patients, all of the patients from the ALPHA-STAR, that original 16 chose to enroll in the ALPHA-SOLAR. So we took that as a good sign that they like what they're seeing in Navenibart for themselves. So 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 ALPHA-STAR Phase Ia -- Phase Ib/II trial.

And does that mean 80% attack reduction? Or do you want to be in that 90% because this is a threshold disease. If you're mopping up plasma kallikrein, it's hard to have an attack. But if you're falling people for years, they're going to have a breakthrough attack at some point. So how do we think about that balance between having enough protection, but also the patients are going to have breakthrough attacks that happens.

Yes, great question. So our target profile as we thought about Navenibart in our design was to target that 80% to 90% attack rate reduction. And so that's what we hope to be able to achieve not only in this -- in the data that we'll share with ALPHA-SOLAR, the long-term extension, but ultimately, what we hope to achieve in the Phase III as well.

And are you seeing -- 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? Every attack I used to have was I'd be down for 2 days versus Oh, now I just have some swelling in my hands. Have you guys looked at severity of attacks on drug?

Absolutely. And so what we've been able to show is that there is a significant reduction in the severity of attacks following treatment with Navenibart. So in the Phase Ib/II trial, we showed a greater than -- I think it was like a 93% to 95% reduction in moderate to severe attacks. So attacks became mild if a patient was going to have them. So that's a huge improvement as well. So we can reduce attacks by 80% to 90% overall, but also the severity of an attack, if it should occur, that's, we think, really a game changer for patients.

And the other, I think, really positive development that I'm not sure if people have appreciated quite yet is your Phase III trial and its design. Can you talk a little bit about what happened with you guys and FDA and then overview of that trial design?

Yes. We're really thrilled with the design and where we ended up with the design. So we're running the Phase III. We're in a single Phase III, we're able to test both the every 3-month and the every 6-month regimens, and that's with a 6-month treatment period. So the primary endpoint of our pivotal is after 6 months of dosing. And so that design enabled us to run a single Phase III to support both of those dose regimens, which is, I think, great, great for patients and great for us as well. And that -- 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. So we had to align all the regulatory authorities around that design, and we got there. And so it's a pretty great design, I think, for this program.

And standard endpoint, right, percent reduction versus placebo at 6 months?

Yes, at 6 months.

How does that work when you're dosing once?

That is the endpoint. Yes. And just to put that in perspective, the dose for the Q6-month regimen is 600 milligrams. And that 600-milligram 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 6 months. But you're right, those patients are getting a single dose.

And then a placebo at 3 months, placebo injection, 3 months?

Yes. So that's right because it's a single placebo. And that's why this is a good trial for patients. And I think the regulators saw that as well as to have to run 2 placebo-controlled trials to support those regimens is not great for patients. And so we really -- great for the regulators to have agreed to that as well.

Have you talked about the hierarchy if you're looking at 3 and 6 months, which one is your primary? And how does that flow through?

So 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. So that's how it is. There isn't a hierarchy of arms. It's -- each arm is individually compared to placebo.

I see. And just given the effect size that should have enough alpha.

Yes. So the alpha, so 0.05 divided by 3 to cover the 3 dose arms, but it's -- this trial was designed to be very well powered, of course, to optimize the chance of success of all 3 of those arms.

I can't recall the Phase III HAE studies failing.

Yes.

If not, has it happened?

Not that I can recall.

So it just becomes how do you compare to the other agents, either approved or in development as well.

Yes. And yes. And so we've just seen -- obviously, TAKHZYRO was one of the first mechanism -- well, there were 2 others before that. But that sort of set the stage, I think, for the efficacy threshold in that 80% to 90%. And we just saw garadacimab and Ionis' Donidalorsen report there is in that range as well.

And we've been covering BioCryst forever. Their drug, ORLADEYO once-daily oral drug has seen tremendous uptake. They just raised guidance again. And I think that's to our previous comments about patients wanting something more convenient. How do you think about any leeway you may have in your efficacy or tolerability profile for something that every 6 months is such a paramount difference between every 2 weeks? Or do you need to have that efficacy profile on par? Like how do you think about that trade-off?

Yes. I think -- so we have good confidence in both the Q3 month and the Q6 month to deliver that 80% to 90% efficacy range. But I agree with what you're saying. For some patients, maybe the most severe patients are 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, so might choose our 2-, 3-month option to make sure that they're getting delivered the best dose to meet their -- meet them where they are in terms of their disease. But I think you're right that -- I mean, ORLADEYO has had a phenomenal launch and sustained growth for that product. And I think that does speak to patients really want something that fits in their lifestyle. And so for patients on ORLADEYO, the equation of thinking about dosing with an injection every 2 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?

Yes. So we'll have to have a safety database as well. And so the Phase III, the way it's designed, so we have our pivotal that's that 6-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. And so 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. So yes, and we haven't given an exact time, but we'll certainly update that as we get enrollment locked down.

Yes. If you guys give guidance for enrollment, you've given a data so we can back out to that. So just if we have data, what have you guys said, I think, first half.

Early '27.

Early '27, so 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. And 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 IIIs. And so I think knows what the challenge is and is up for it. And so we certainly -- when we designed the strategy behind the Phase III, we 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 Ib/II trial rolled in faster than we thought it would. And in the U.S. and Canada, we originally thought we're going to have to open sites in Europe to enroll that trial, but it enrolled quicker than we could get sites opened up outside of the U.S. So that was a good sign. I think the other thing, we designed the Phase III 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. And all that together is great. But I think one thing that we're seeing is a lot of enthusiasm for Navenibart as well. And I think the profile of Navenibart is something that has been attractive to patients. And so that's helping, I think, with the enrollment.

And maybe last question on Navenibart. Can you talk about the research you've done about potential uptake and the opportunity given every 3- and 6-month dosing and how that fits in versus other options out there?

Yes. So we've done market research, and we've also seen market research done by some other external groups...

Including us.

Including you, yes. And I think it points to that, that both the every 3 month and the every 6 month appear to be real step changes in terms of how people think about treating this disease. And 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. So we're pretty optimistic about our potential to become that market-leading product in the space.

So Navenibart is what caught our attention. And then when we started looking at STAR-0310 as well, also, I think, a pretty compelling profile when we think about atopic dermatitis and the size of that market. But we dug in a little while back. We had Phase III data for another OX40 agonist that didn't look that great. Why is STAR-0310 going to be different?

Yes. I mean we're fortunate. This is a mechanism and an area where actually learning from the programs ahead of us was really important. When we -- so we designed 310 in 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. And I think that's what we have with STAR-0310.

What did you do?

So with -- as we think about rocatinlimab, we have engineered STAR-0310 to, we hope, avoid the safety tolerability issues associated with T cells killing that rocatinlimab was an antibody that was engineered to kill T cells. And as a result, you see fever and chills as one of the safety tolerability effects in the trials. And in a disease like atopic dermatitis, that's just not going to fly. And 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, so open up that therapeutic window.

And what's your duration -- your target duration for STAR-0310?

Yes. So that's another aspect of the program. We also engineered STAR-0310 for a long half-life. So it's also leveraged the YTE half-life extension technology. Our hope with this program is we could dose as infrequently as every 6 months. And that's an important aspect of the OX40 mechanism as well. Not only do we think we can address 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. And that's one of the real excitements about the space.

And you mentioned earlier, you have a Phase I ongoing data 3Q, but healthy volunteers. Are we going to learn enough? What are we going to see?

Yes. So this Phase Ia 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. And so what we know about the other programs, so the rocatinlimab program is in a healthy subject trial, greater than 50% of the subjects in their trial had fever. So likely because of the T cell killing. So we'll 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 2 things combined can really lead to our ability to drive efficacy.

So if we see 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 -- keep it simple, stupid. If we see that, we're on the right track.

Yes. 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, the EC50 and EC90. So okay. And then can you remind us in the last little bit of time, your current cash position, runway, including catalyst that we talked about, but maybe just putting a button on things to look forward to over the next 12, 18 months?

Yes. So we're in a good -- strong cash position, cash into mid-2027, so importantly, through the key milestones for the Navenibart Phase III program. So we'll get through our top line data with that program. That's really important and certainly a priority for the program. Upcoming milestones, so we have the ALPHA-SOLAR long-term extension data from the Navenibart program that will read out midyear, and that will be data on safety, tolerability and efficacy of Navenibart following every 3-month dosing or every 6-month dosing. And so we have patients who now have been on Navenibart for more than 18 months. So we'll have that data midyear. And then for STAR-0310, the major milestone is the Phase Ia healthy subject data in Q3.

So stuff in the next 6 months even that we'll be looking forward to. So very exciting times. Jill, thanks again for joining us, and we look forward to catching up with you guys with your first quarter update, but then also with the SOLAR extension data.

Great. Thank you very much.