everyone, for attending Jefferies London Healthcare Conference. My name is Kelly Shi, one of the Biotech Senior Analysts here. For this fireside session, we are very pleased to have Jill Milne, Chief Executive Officer, and also Dr. Chris Morabito, Chief Medical Officer from Astria. Welcome, both. Thank you. Thank you. Maybe start off with a high-level question. Could you give an introduction of the company to the audience who are not very familiar with the story ongoing at Astria and also your strategy of developing first choice therapeutics in allergic and immunological indications? Yeah, absolutely. So at Astria, we are focused on allergy and immunology. Both programs that are currently in our pipeline are targeting diseases in those therapeutic areas. Our pipeline was built with the strategy in mind of working on established mechanisms, so mechanisms where there is strong scientific rationale supporting that particular mechanism in the disease state that we are targeting. However, an important piece to that strategy is that for the mechanisms and programs that we work on, that we see potential for best in class or to develop first choice therapeutics. And what do we mean by first choice? We mean that both physicians and patients will choose our products first because of the competitive efficacy, good safety tolerability, as well as low treatment burden. And I think both of the programs in our pipeline, navenibart in hereditary angioedema and STAR-0215 in atopic dermatitis, both fit that strategy extremely well. Fantastic. Now start with the leading program, STAR-0215 in prophylactic HAE. Could you set the stage by providing an overview of the data you presented early this year and what was the rationale for three cohorts at three different doses? Yeah, I'd be happy to do that. So STAR-0215, also known now as navenibart, is currently in a phase 1b/2 trial, and that's a proof of concept dose range in clinical trial from which we reported initial results in March, and I'll review those with you in a minute. To set the stage, this navenibart is a YTE modified monoclonal antibody against plasma kallikrein. Plasma kallikrein is an established target. The market-leading medicine, lanadelumab, is also a plasma kallikrein inhibitor in HAE. It's given every two weeks or every four weeks in some patients. With navenibart, we see a half-life of about three months in people, and that now allows us to potentially administer navenibart every three months or every six months to achieve competitive efficacy, which will significantly address patients' burden of disease. And then based on phase 1 data, we chose three dose cohorts for this ALPHA-STAR study, the ongoing phase 1b/2 trial, in order to test that hypothesis. So in this ongoing trial, we've had now three dose cohorts completely enroll, and we expect full results to be shared from this trial later on this year, in which we test single and then up to two doses over up to nine months to look at overall effectiveness in reducing attack rates in patients. So typical trials at this stage in this space are much shorter, maybe a couple of months. We're up to nine months, and we're looking at over that entire period, can we achieve competitive efficacy? The initial results that we presented back in March indicate that yes, indeed we can. So one or two doses of this medicine followed up for about six months at this time point reduced attacks from baseline 90%-96%. So that's a significant reduction compared to baseline. And again, it's just one or two doses for up to a six-month time of follow-up. Fantastic, and we will have a longer follow-up data by the end of the year from both three-month and six-month cohort, so what kind of attack reduction rate or maybe attack-free rate would be considered as an optimal result? Yeah, so we will have data later this quarter in the coming weeks, the final data from the 16 patients that initially enrolled in the ALPHA-STAR phase 1b/2 trial that Chris just reviewed, and what we would expect from the data is to see similar levels of efficacy that we saw in the interim analysis that we reported at the end of March, and so we would expect in that 80%-90% attack rate reduction at three and six months of dosing and similar PK/PD profile as well as safety and tolerability. Great. And compared to the current therapy on the similar MOA Takhzyro, you already delineated differentiation on treatment interval, but overall clinical profile, what kind of differentiation could we expect as well? Yeah, I think for comparing to Takhzyro, we think there are a couple of areas where we differentiate favorably from Takhzyro. So you, of course, the one that's top of mind based on the YTE half-life extension is the lower treatment burden with Takhzyro being dosed most often in patients every two weeks. We expect to be able to support a profile of dosing once every three months and a profile that could support once every six-month dosing. So a significant improvement, and I think goes definitely a step further in normalizing the lives of people living with HAE. In addition to that, we believe there is potential to differentiate on efficacy from the perspective of attack-free. We believe that because the longer that we can keep patients' drug levels above a threshold that keeps the plasma kallikrein levels suppressed, we think we can keep patients attack-free for longer durations of time. That's something in our phase three that will be an important secondary endpoint for us. Finally, I think from a treatment burden perspective, we took great care in developing the formulation for navenibart to make sure that we could support a formulation that offered pain-free injection. We are aware that some patients experience pain with injections of Takhzyro, and we believe that may be due to the citrate buffer that's included in that formulation, and that's obviously been seen before in other monoclonal antibody formulations. Could we also talk about phase three clinical trial design in details in terms of cohorts and treatment interval, patient number, or maybe a timeline you anticipate to release top-line data? Yeah, so we are progressing to phase 3. That is the plan based on the initial results we shared and just discussed now, and we anticipate starting that trial in Q1 2025. Pending regulatory feedback, we expect this to be a treatment duration of about six months in which we test the overall effectiveness of navenibart given to patients, including adolescents through adults with HAE, to look at time normalized reduction in attack rates and also to look at the proportion of people who are attack-free. We look forward to sharing many more details about that phase 3 once we get the final design feedback from regulatory authorities throughout the world. It is going to be a global study, so we have many regulatory authorities to deal with here as we collect that feedback, and we'll share more information about those cohorts at that time. Okay. Just to confirm, you mentioned for pivotal will be only every six months? No, we haven't declared that specifically. Oh, I see. Yeah, no, but the treatment duration will be six months. We think that this could be a drug that's given every three months and six months and look forward to bringing both to patients. This is a variable disease. We want to make sure patients have the drugs they need, and our pivotal program will be sure to deliver on that. I see. Thank you for the clarity. For the every three months and every six months, how do we think about the timeline? It will be like a sequential or parallel, and so how this is going to be carried out if we're going to start with two different dose regimens? Yeah, so we'll be very excited to share the final design of the phase 3 in the coming weeks. Once we have that, I think certainly a very exciting time for the program. Our intention is to bring both forward, and working through the final details of how best to do that most efficiently. Okay, great. And also HAE is a very active landscape now, and we saw a new data drop and also the regulatory update. And so what is your view right now compared to 12 months ago? Yeah, I mean, I think from the view of the potential of navenibart, I think it's encouraging from that perspective that I think navenibart more than ever has the ability to be the first choice preventative therapy in HAE. And certainly Takhzyro continues to be the market leader. As Chris mentioned, we are targeting plasma kallikrein with the monoclonal antibody just as Takhzyro does. So I think we have in navenibart something that no other program has. We have a trusted mechanism, a trusted modality, robust efficacy on par with the market leader, the potential to differentiate on attack-free and extremely low treatment burden. So a combination that I think differentiates incredibly favorably across all of the programs currently marketed, but importantly, those in late-stage development as well. When we talk to the physician community, what kind of aspects they care the most in terms of bringing the benefit to patients, efficacy, safety, treatment burden? So if we have to rank them, what kind of preference do you hear from physicians? Yeah, efficacy, treatment burden, and the assumption is that all of these medicines have some degree of defined safety. This is a very tight-knit clinical community. Patients and physicians interact very closely. Any perceived safety risk is going to be a concern. To date, we trust this mechanism. There's plenty of data to suggest that it's well trusted. So now our onus is to demonstrate that we can be as effective as the market-leading medicine, so 80%-90% reduction in attacks, and then ultimately demonstrate that we could be delivered less frequently and maintain that degree of efficacy. Great. And looking to the competitive landscape, we also have multiple agents being developed in on-demand HAE market. And how do you see prophylaxis versus on-demand and development in the next three to five years? And also the overall HAE market opportunity, if we have to put a number on that, what would that be? Yeah, I'll start there and work backwards on your question. So in terms of the overall market opportunity in HAE, this is a large market for a rare disease. So we anticipate this market to continue to grow, especially in the area of the preventative prophylactic therapies. We expect the market to be over $4.5 billion by 2027. And I think as we think about the market from preventative therapies and on-demand, I mean, on-demand are in the treatment guidelines that patients should carry an on-demand therapy with them. However, certainly from what we've seen in our ALPHA-STAR phase 1b/2 trial is a market decrease in the utilization of on-demand therapies for patients on navenibart, and that's due to the robust attack rate reduction we saw. So I would anticipate that over time, as therapies like navenibart go forward, that we might see less utilization of on-demand therapies, but there still will be utilization of on-demand, certainly. Great, and maybe it's still too early to talk about pediatric programs, but if you have any thoughts on that, if you don't mind to share? Yeah, so the adolescents, we plan to include adolescents in the phase 3, so that would be 12 and above. And then the next group of patients that we would consider is that group between two and 12 years old. It is a little bit too early to talk about it publicly, but this is a genetic disease. It is a disease that can be diagnosed in early childhood. We believe it is important to have a medicine available for that patient population and think that our profile would be something that would suit growing kids well. So look forward to being able to bring this forward and look forward to sharing more plans about that in the future. We also saw some manufacturing setback from the competitive landscape. Curious, any thoughts you have on your manufacturing strategy? Yeah, so we're familiar with the garadacimab CSL program, receiving a CRL for manufacturing issues, and obviously, manufacturing is something we take very seriously. We have an incredibly experienced team, a team that has taken many biologics all the way through to commercialization, and so it's something that is certainly a focus for us. We are using well-known CDMOs that we can take us all the way through to commercialization, and so something we will continue to keep a lot of attention on. Great. And switch gears to STAR-0215 program, which is OX40 antagonist and targeting atopic dermatitis. And maybe first, could you give us an overview of the molecular design and how do you see the potential differentiation from other OX40 programs in AD? Yeah, great. So it is an OX40 receptor antagonist. It is a monoclonal antibody, and it has Fc engineering. So it's demonstrated already to have high affinity to OX40 receptor in the single nanomolar range. We've demonstrated already, and I'll talk about this more in a second, a high degree of potency in vitro against T cells, activated T cells, and the cytokines that they release. The YTE modification is in the Fc region on this, and it again will, we expect it to prolong half-life in humans. We've demonstrated to date in non-human primates that there is about a two and a half- to three-fold prolongation of half-life up to 26 days in NHPs. And look forward to starting our phase 1 study next year where we'll be able to demonstrate in humans what that half-life is. That YTE modification, in addition, decreases IgG1's native antibody-dependent cellular cytotoxicity, which we think will confer clinical advantage, so to address your question about differentiation, we think that there's a potential with 310 to be best in class on efficacy, best in class on safety, and best in class on dose frequency and administration. The efficacy and safety come in large part because of the high potency and because of the decreased antibody-dependent cellular cytotoxicity, which ADCC by itself is associated with adverse events and discontinuations in one of our competitor programs, and it restricts the therapeutic window such that doses must be determined that may provide some efficacy, but would also decrease the amount of potential safety risk. For us, without this ADCC liability, we open up the therapeutic window, can drive doses higher, and look forward to being able to potentially demonstrate efficacy superior to what's being seen in phase three with a competitor program to date, and then dose frequency, of course, enabled by the YTE. Great. And there was a recent data drop of phase 3 OX40 program, rocatinlimab. And so when you look at efficacy and the safety, any read-through actually to your program? Indirect read-throughs, not direct. And this is important. This is that competitor program I was referring to. This is rocatinlimab, which is currently in phase 3 in atopic dermatitis. There are seven ongoing phase 3 trials with this. The very first of those phase 3 trials read out earlier this year. We expect the second one to read out at some point between now and the end of Q1. The rocatinlimab targets the OX40 receptor, just like 310 does, but it has enhanced ADCC through afucosylation on the Fc. So this attracts cells to kill the T cells. The T cells, as they die, release cytokines, causes fever, chills, flu-like symptoms, and ultimately leads to adverse events that can be associated with discontinuations. And in fact, in their phase 2b trial, efficacy was quite high at a Q2 week dose, but so were discontinuations due to adverse events. phase 3 showed less efficacy than was demonstrated in phase 2B, and we think in large part because they went from a Q2 week dose in phase 2B to a Q4 week dose in phase 3. We believe this is because they're trying to target this narrow therapeutic window. They're trying to get efficacy better than placebo, which they achieved, while reducing the risk of discontinuations due to adverse events. We think that's related to ADCC, which we've addressed in the molecular design of 310. Fast forward to phase three trial, what kind of ultimate clinical profile on both efficacy and the safety would make it compelling next to Dupi in AD? Yeah, great. Yeah, so we think, importantly, I think, showing EASI-75 scores that are competitive with Dupixent, if not better. I think this mechanism and what attracted us to the OX40 mechanism is the potential for the broad effects across atopic dermatitis. And so where Dupixent and other therapies in late-stage development are approved target the TH2 aspect of atopic dermatitis, the OX40 mechanism has the potential to target broader T cell populations that are implicated in the pathology of atopic dermatitis. We believe the OX40 mechanism has the potential to have a broader reach across atopic dermatitis. I think initially what we would anticipate is seeking a broad label in atopic dermatitis to treat patients with moderate to severe atopic dermatitis. I would imagine initially this mechanism would likely come after Dupixent because Dupixent has established itself really as the first-line biologic in this disease area, rightly so. It's shown good efficacy. I think OX40 has the potential to show greater efficacy, but importantly also to show disease-modifying aspects as well. We are awaiting for this OX40 program and when do we expect the first clinical data? Yeah, so we are on track to file an IND with the STAR-0215 program this quarter and be in the clinic early next year in Q1. And then would expect initial results from that phase 1a healthy volunteer trial in Q3 of next year. And we think that data will be informative on the potential profile of STAR-0215 in terms of PK and dose range. Would you also provide a cytokine analysis for that healthy volunteer trial? Yeah, we're working through right now the final details of what will be provided from a PD perspective as well. Fantastic. We're going to wrap up here, and thanks for a very insightful discussion, and looking forward to the next 12 months. Thank you.