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

Good afternoon. Welcome to the Astria R&D Day. [Operator Instructions] At this time, I would like to turn the call over to your host, Dr. Jill Milne, Co-Founder and CEO of Astria Therapeutics. Please go ahead, Dr.

Hello, everyone. I'm Jill Milne, CEO of Astria Therapeutics. We are very glad to have you here with us today at our first Astria R&D Day. I will start today's event by providing an introduction to our company and our vision for how we believe that our lead product candidate STAR-0215 can positively impact the lives of people living with hereditary angioedema or HAE. I would like to note that during today's event, as mentioned here, we will make forward-looking statements related to our business based on current and future expectations. Actual results may differ from those indicated by these statements as a result of a variety of risks and uncertainties, including those discussed in our most recent Form 10-K and our subsequent SEC filings. Such statements represent our judgments as of today, and we undertake no obligation to publicly update any forward-looking statements, except as required by law. At Astria, we are developing therapeutics for patients with rare and niche allergic and immunological diseases. Our commitment to patients drives everything we do. Our mission of bringing hope with life-changing therapies is propelled by the voice of the patient. We have listened and will continue to listen to the communities of those impacted by HAE. We are guided by their experiences, and we work to create therapies that both treat their disease and improve their quality of life. Shortly, you will have the opportunity to hear directly from people living with HAE. As we go through our program today, these are the key points that we want you to keep in mind about why we believe STAR-0215 is an exciting opportunity. It has a differentiated profile that we believe can positively impact patients' lives. We are on track with our upcoming milestones, including preliminary results at year-end. And we believe there is a significant commercial opportunity for a product like STAR-0215. Beginning with the profile, our lead program, STAR-0215 is a monoclonal antibody inhibitor of plasma kallikrein, designed to provide long-acting effective attack prevention to treat people living with hereditary angioedema or HAE. We see STAR-0215 as an opportunity to develop what we believe could be the most patient-friendly preventative therapy for HAE with dosing once every 3 months or longer. Our goal is to reduce both disease burden and treatment burden. We have made exciting progress over the past year with bringing STAR-0215 through completion of an IND filing and into the clinic. At this point, all subjects have been dosed in our Phase Ia trial of STAR-0215 in healthy subjects. We see this trial as an opportunity to inform on the differentiated profile of STAR-0215 as a potential best-in-class treatment for HAE. The trial is monitoring safety and tolerability and we anticipate the results will be informative in terms of pharmacological activity and the half-life of STAR-0215. Preliminary results are anticipated at year-end. Our research shows that there is a need for a product like STAR-0215 in the HAE market from both a patient and physician perspective. The global HAE market was greater than $2 billion last year and is expected to double to $4.5 billion by 2027. This growth is predicted based on patients being diagnosed earlier, more patients taking treatments to prevent HAE attacks as well as the expansion of [indiscernible] therapies in more geographic regions. We have a clear path on delivering on our vision for STAR-0215. Recently we had our IND STAR-0215 accepted by the FDA and subsequently launched our Phase Ia clinical trial in healthy subjects at the beginning of August. As mentioned previously we expect preliminary results from this Phase Ia clinical trial at year end and plan to initiate a global Phase Ib/II clinical trial in people living with HAE in the first quarter of 2023. The primary goals for this planned Phase Ib/II trial are to demonstrate proof of concept in HAE by assessing safety and tolerability, establishing prolonged half-life demonstrating durability of inhibition of plasma kallikrein activity and providing an assessment of the impact of STAR-0215 on HAE attack rate. Correspondingly, we refer to this trial as a proof-of-concept trial. If successful, we plan to initiate a pivotal trial to efficiently progress STAR-0215 to potential registration. This planned development path would enable us to reach HAE patients as quickly as possible as we work towards our goal of changing the way that people live with HAE. I will now introduce our speakers and their topics for today. We are pleased to have Dr. Marc Riedl joining us to speak about the HAE current treatment landscape and opportunity to improve patient experience. Dr. Riedl is Professor of Medicine and Clinical Director of the U.S. HAEA Angioedema Center at the University of California San Diego, where he serves as Clinical Service Chief for allergy and immunology. He is a member of the U.S. HAEA Medical Advisory Board and the Immune Deficiency Foundation Physician Advisory and serves on numerous editorial boards and scientific committees as well as appointed expert panels for the FDA and NIH. With me today from the Astria team, we have Andrew Komjathy, our Chief Commercial Officer, speaking on HAE market insights. Next, Andy Nichols, our Chief Scientific Officer, will speak about the discovery and characteristics of STAR-0215 and review pre-clinical data from the program. Lastly, we have Chris Morabito, who joined us recently as Chief Medical Officer, who will discuss our clinical development plans and expected year-end results for STAR-0215. We are deeply appreciative of the opportunity to open today's event with a video that shares firsthand the experience living with HAE. In the video, you will meet 3 people who are HAE advocates and patients themselves. The video begins with these individuals sharing stories of their first attacks and managing their disease today. The video concludes with the immense efforts the US Hereditary Angioedema Association and HAE International are making to benefit the HAE community. [Presentation]

Thank you for watching. The perspectives of patients are essential in our mission to bring hope with life-changing therapies and why we believe STAR-0215 can make a positive impact for those living with HAE. I will now turn it over to Dr. Riedl to speak about the current treatment landscape and opportunities to improve patient experience. Dr. Riedl?

Well, thanks very much for that introduction, and good afternoon or good morning to everyone. Where -- depending on where you are in the world these days. It's really a pleasure for me to join the presentation this morning for me on the West Coast. I'm Marc Riedl, I'm from the University of California San Diego, as you heard, and I've spent 20-plus years working in the field of hereditary angioedema. I spend most of my clinical time and also been heavily involved in the translational and clinical research, trying to advance therapies for individuals affected by HAE. And I'll just say that it's both inspiring and humbling to follow that video, there's really no comparison to sitting and listening to people and families who are affected by this condition. But I will do my best to provide you some additional background and context for the discussion today. These are my disclosures different companies that I've worked with in the field for transparency's sake. So what I hope to uncover in the next few minutes is the following. I want to give you some background on the clinical presentation and the impact of HAE as you just heard from some patients, but share with you what we see in caring for a large population of people with HAE. I'll run quickly through the evidence-based guidelines for recommendations for treatment of HAE because this is where we stand currently in managing the condition. And finally, I'll talk a little bit about the unmet needs and opportunities that -- where I think we can still advance our therapies with the ongoing research and clinical trials. So first, just to level set the conversation. As you likely know, the hallmark of hereditary angioedema are these protracted and severe angioedema symptoms that occur without hives without itching and of course, have a very different path of physiology from the much more common allergic causes of angioedema. And so on the right here, you can see some representations of the actual symptoms caused by HAE. These include very severe swelling episodes of the skin, that could be anywhere, but it often affects the head and neck or the extremities the gastrointestinal swelling, which is represented in the middle panel by endoscopy of the small bowel that becomes very obstructed and extremely painful and then lastly, the airway events, which are represented in the lower right corner, these are serious life-threatening and fatal if not recognized and treated effectively. And I think we can never forget in an era where we still -- we have effective treatment for these attacks. This is a disease that still kills people. It is a life-threatening condition. These episodes are protracted, as I mentioned. They often last for 3 to 5 days, if not treated, and they sort of have a slow onset and slower offset which is very debilitating, but does give us an opportunity to act and try to terminate that episode. And as you know, these episodes do not respond to the usual allergy treatment. So antihistamines, corticosteroids, epinephrine, all the messiness that people typically get when they go to the hospital with angioedema do nothing to relieve these symptoms because they're not treating the proper mechanism or pathophysiology. We'll talk a little bit about the unpredictable nature of these episodes. They're very unpredictable and highly variable. And this is a huge burden for patients to live with because they really can't predict how frequent these are going to occur or when they might occur. And there are some triggers we discussed with patients. Those include stress or trauma, they include certain medications like estrogens or ACE inhibitors. And so there are some non-medicinal or pharmacologic management measures that we take, but mostly we rely on medications these days because of the severe and unpredictable nature of the condition. Lastly, as you know, this is a familial disorder, hereditary disorder and it is autosomal dominant. So when we diagnose 1 patient, it's very likely that we find affected family members. Just a reminder, this is the pathophysiology or mechanism of hereditary angioedema. It is at the end of the day, a bradykinin-mediated condition caused by dysregulation of this so-called contact system or kallikrein-bradykinin system. And so in most cases, the deficiency of C1 inhibitor protein, which is represented by the pink circle here leads to overactivity of Factor XIIa and kallikrein and produces excessive bradykinin, which leads to the vascular leak and the clinical angioedema symptoms that we see in patients. And so of course, our treatments that have been proven effective and those in development are based on this well-established pathophysiology for the cause of HAE. Now most of the work in hereditary angioedema has focused on type 1 and type 2 HAE as I've mentioned, these are the most common types of hereditary angioedema caused by this deficiency of C1 esterase inhibitor, the couple of flavors here in type 1. There's not enough protein made in sufficient quantities. In type 2, the protein is produced, but it's misfolded due to the mutation and lacks the proper inhibitory properties. These 2 types basically behave the same, have a very similar phenotype in all of the clinical trials that we have to date for FDA-approved medicines have looked at these 2 subtypes of HAE. I will mention briefly we won't focus on it, but there is yet a third subtype of HAE that's been described, so-called HAE with normal C1 inhibitor -- this results in very similar type of swelling, a similar phenotype. However, it does not appear to be due to C1 inhibitor deficiency, and this remains a very ripe area for research, lots of activity going on in the translational world, trying to determine the underpinnings or pauses of this type of HAE. We do have a few mutations that have been described, but many patients that appear to have this condition still have an unknown mechanism or pathophysiology. So let's shift now to talk a little bit about current HAE management. And I'm going to refer to the evidence-based guidelines referenced on the bottom of this slide. These are the U.S. HAE and Medical Advisory Board guidelines or the so-called U.S. guidelines. Certainly, there's also international guidelines, which you may see referenced in some of my other slides. Suffice it to say, these are extremely similar. They basically lay out the same treatment principles because they look at the same body of evidence of clinical trials. So we have 3 main strategies that we use in our toolbox to manage hereditary angioedema. Those are represented here, and I'll briefly run through these. As we talk about these, though, it's important for me to mention that we use these in an individualized fashion. And so because there's so much variability with how people are affected in terms of frequency of symptoms, type of symptoms, how it affects their lives. We really do tailor these strategies for each individual patient. However, the first step in managing HAE is to establish an on-demand treatment. This is required for all patients, and I'll show you very briefly the medications that we use. But of course, these are medicines used at the time, at the onset of an attack to stop that attack and shorten the duration, prevent the severe episodes that can become very disabling and life threatening. Secondly is long-term prophylaxis. And as you may be aware, this is where a lot of the research has spent its time in the last few years developing better ways and more effective and more tolerable ways to prevent these attacks. And I think this is a natural evolution in medicine as we deal acutely or reactively to the symptoms, but then we look for ways to prevent those symptoms. And so we'll talk briefly about some of the options we have for long-term prophylaxis, this may not be used in every patient, but it's increasingly being used more frequently given more and more evidence of as I said the benefits of preventing these episodes. And the middle column here, I'm not going to talk about, but this is short-term prophylaxis, giving a medicine prior to a medical procedure or some other event that's known to have a very high likelihood of triggering HAE symptoms. Now as I mentioned, of course, the therapies that we have are based on the understanding of the contact system and the dysregulation that causes brain decline in their own production. And so we have several mechanisms of action for current medicines. We have C1 inhibitor replacement products either are used acutely or preventatively or we have medications that target plasma kallikrein started with ecallantide years ago as an acute medicine but more recently, effectively used with lanadelumab or berotralstat for long-term prophylaxis. And then we have an acute medicine that targets the B2 receptor, the bradykinin 2 receptor and blocks the effects of that excessive bradykinin on the endothelium to prevent vascular leak. You see also androgens, those androgens are still listed because there is efficacy data. They are approved by the FDA. No one really knows how androgens work to be blunt. They do seem to be effective, but as I'll show you, they've been really been relegated to a second-line medicine now due to the considerable toxicities and side effects that we've seen over the years. Very briefly, these are the FDA-approved acute therapies that we currently use to manage HAE. A lot of information on this slide, but suffice it to say, again, we have C1 inhibitor replacement products that are infused intravenously at the time of an episode. We have ecallantide which is given subcutaneously, but must be given by a health care provider due to a risk of anaphylaxis and then icatibant the B2 receptor antagonist, which again can be given subcutaneously at the time of an attack. And each and every patient that we care for must have at least 1 of these medicines readily available to manage their symptoms, which, as I've mentioned, can be unpredictable and severe. These are the principles, the guiding principles in the evidence-based recommendations on acute treatment just by way of review, really, all attacks are considered for on-demand treatments because any and all attacks can be debilitating and evolve to life-threatening symptoms. We really encourage early treatments. Again, the earlier the medicines are used, the less likelihood there is for severe complications and the more quickly people return to their normal activities. I've already mentioned the first-line medications that are FDA approved and recommended in the guidelines. And really, patients should have medication to treat at least 2 attacks and have this readily available at all times. This is due to the fact that, again, these attacks can occur in quick succession in rare cases, and it does take time to refill these medications. As mentioned earlier, self-administration is important because of the fact we want to treat early. And so any of the medicines that are licensed for self-administration, we teach patients to use those to treat their attacks at the time of onset so that they can rapidly get relief without having to go to the hospital, a clinic or somewhere where invariably, there will be delays in them getting their effective therapy. All right. The other very important strategy increasingly used is the long-term prophylactic therapies. Again, a busy slide, but just for reference, we have a number of FDA-approved treatments to prevent HAE attacks. We have a plasma-derived C1 inhibitor products initially approved and used intravenously but now increasingly used subcutaneously. This treatment must be given twice a week for maximal efficacy. The monoclonal antibody, lanadelumab, targeting plasma kallikrein. This is subcutaneous and is initially given every 2 weeks can be extended to every 4-week dosing if patients are attack-free for 6 months or longer. And finally, the most recently approved medication berotralstat, which is an oral plasma kallikrein inhibitor 1 oral dose daily, which has been useful, but based on clinical trials has not shown quite the same evidence of efficacy as we -- as was seen with lanadelumab or the subq C1 inhibitor. And then some older medications data sales and androgen, which I mentioned, is approved for prophylaxis but really used increasingly less because of the side effects. There's a laundry list of these, and I've listed some of them here. So there's a lot of monitoring and toxicity concerns with androgens. Tranexamic Acid is really only used in the United States for HAE with normal C1 inhibitor, which again is not the focus of our discussion today, but there is evidence of preventative effects for this antifibrinolytic medicine in that particular subset of patients. And so if we go back to the guidelines, here's what they say about the guiding principles of long-term prophylaxis that really patients to be evaluated for this treatment strategy in every visit this is because HAE symptoms do evolve, and we want to make sure that patients are aware of their options and use long-term prophylaxis if we believe the disease burden to be great enough for implementing that and also considering the patient preference, how do they wish to manage this chronic condition. I've gone over the first-line long-term prophylactic therapies, which are recommended in the guidelines. And then as I've mentioned, androgens have been relegated to a second-line prophylactic treatment based on side effect profile. The other important comment is that long-term prophylaxis really needs to be adjusted over time in many patients. And so because of tolerability or side effects or efficacy or even the natural course of the condition, there are times when we frequently will make adjustments to the long-term prophylactic regimen. And so this needs to be reviewed on a regular basis. Now I've showed you sort of the tools that we have to manage HAE at presence, and there's been a lot of interest in looking at how we're doing, are we accomplishing the goal of improving symptom control, but perhaps more importantly, improving people's lives. And so we do have some validated measures of this. You see it at is the angioedema quality of life score. What I'd like to show you is that there's emerging evidence and increasing evidence that prophylactic strategies do, in fact, improve control of the condition as well as quality of life. This is a small study out of a German center, and there's a lot of numbers on this slide, but the important fact here to note is that if you compare patients that are on just on-demand treatment, treating their attacks when they occur compared to those that are on long-term prophylaxis. You can see that by any number of validated measures, including angioedema quality of life scores, control tests as well as anxiety and depression scores, long-term prophylaxis has significant benefits over just treating these attacks when they occur. Likewise, this is a U.S. study of over 1,000 patients that were surveyed using different types of treatments. So a little bit of a busy slide. But if I walk you through these 2 columns on the left are patients just treating their attacks, those that have had at least 1 month without an attack and those that have had at least 3 months without an attack. The middle 2 columns are all patients on prophylactic treatment, including those on older therapies like androgens again, 1 month without an attack, 3 months without an attack. And on the far right, these are patients that are on the newest or novel precision prophylactic therapies that we just discussed. Again, 1 month attack-free or at least 3 months attack-free. And what you'll appreciate if I add in this arrow is that as you go across for the more modern and on to the prophylactic therapies and those that are better controlled, they have the best quality of life. So there seem to be very -- in a large data set very clear trends of benefits for long-term prophylactic therapy, which I think supports the fact that we are seeing more and more utilization of long-term prophylaxis, more patient preference moving towards that strategy. Now the last thing I'd like to mention is the burden of disease. And again, as we've evolved our treatment from just trying to keep people from dying from HAE and trying to keep them out of the hospital, we've recognized that there are lots of issues we need to explore and try to improve in managing HAE. And this is a nice paper for Aleena Banerji colleagues just showing a number of domains that are important to consider. The chronicity, the unpredictability, the fact that these treatments are sometimes hard to access or sometimes hard to use. And then all of the costs and impact on activities or quality of life measures. And this has been taken now to a Delphi initiative, where experts from around the globe sat down and said, what are our goals now. Now that we have these tools and continue to work towards better treatments. What can -- what should be the ultimate goal. And you can see this almost unanimous agreement that we should be aiming to normalize patients' lives achieving total control of the disease, meaning ideally, no attacks at all that we should really listen to patients that they should have input on how they want to approach this and how they're doing. And lastly, that we really do need better tools, and we need to use tools to look at the impact of these therapies and measure how we're doing in terms of normalizing life. Now we've gone back to patients and ask them how they're doing. This is a survey of 75 patients that are on modern treatments and asking them how are you doing with that treatment. And part of what we hear is that there is a burden to the current treatment that they've kind of learned to tolerate the difficulties that they deal with in taking these medicines. And again, the total overall population is in the dark green here. So nearly 90% of patients feel like they've had to learn to tolerate, some difficult aspects of their treatment. They try now to think about how demanding their HAE treatment is -- and to some extent that they do tie of the frequent injections or infusions, which is still really the primary way that these medications are administered. So given these medicines a couple of times a week or a couple of times a month, does lead to some treatment fatigue. We've also asked patients and physicians what's most important to you when you're looking at your options for HAE therapy. And I'll show you the patient data first in these green circles. I'm happy to see they do care about effectiveness. That's still the most important thing to them. But interestingly, the cluster of things that's next most important for their priority is how is the medicine given and what's the dosing schedule? So how is it given? How often do I have to take it they do care about side effects, but actually that slots in behind the route and dosing schedule. For physicians, probably not surprisingly, we're most interested in efficacy and safety. But a majority of physicians will also recognize this is important. The patient needs to be able to tolerate the treatment adhere to the treatment and the burden of therapy needs to be as tolerable as possible for patients to buy into this and actually get the benefits of the therapy. So what I'm driving at here is that we're in an era now where we really have some options to individualize HAE therapy. A lot of that comes in knowing your patients, knowing how this affects them in terms of the pattern or the phenotype that they present with the symptoms. But increasingly, we're factoring in quality of life, which is not only the burden of disease, but also the burden of the therapy that we're recommending or prescribing. And then, of course, we have different medications that have different profiles. I think efficacy and safety are always going to carry the day. But there are these other factors, including dosing schedule, root of administration and patient preference that are increasingly a major part of our conversations. So because of that, as you've heard and will hear -- we don't think we're done yet with developing HAE therapies. There's improvements to be made. Those include less frequent dosing. There is work going on with oral medications and finally, in the very early stages some work looking at gene therapy as a preventative strategy for HAE. So I'm going to wrap up just taking it back to the clinic. I think this is where I sort of begin and end with my thought process, sitting with the patients. We used to just ask the generic questions, how are you doing and then tell me about your attacks, how often did you end up with a hospital? Did you have to use your rescue medicine? We're becoming more refined in those conversations. And I think the question now is, is your plan working for you? Are you in control of your condition? Do you have concerns about the medications, either side effects or tolerability or are you able to easily adhere to the regimen that's being prescribed? And then finally, what are you doing -- not doing or not doing well. And we heard about this in those vignettes, the videos -- are you able to work and pursue the career that you want? How is your family and social life? Are you exercising? All the things that are important to us is human beings, that's actually what we're evolving to, and I'm excited to see what's happening with this company and others to try to move us closer to this goal of normalizing life for patients. So with that, I'll finish. Thanks for your attention, and I'll turn it back over for the rest of the program.

So thank you, Dr. Riedl. Greatly appreciate it. As Jill mentioned in her opening remarks, the global HAE treatment market is well established and commercially attractive. Last year, global revenues were $2.3 billion and are expected to almost double by 2027. This growth is driven primarily by 3 things: the increased awareness of the disease, which has enabled earlier diagnosis than what Henrik Troise and Tony spoke about earlier this morning and an increasing number of patients who have decided to take preventative treatments and the broader global expansion of access to available treatments. In addition, as Henrik Troise, Tony and Dr. Riedl also shared this morning, HAE is a devastating rare disfiguring and potentially life-threatening disease. There are published data that continue to support that despite the advent of new treatments, both patients and health care providers aren't satisfied with and are looking for treatments that are both effective in managing the disease and also reduce the burden of treatment. As mentioned earlier by Dr. Riedl, one of the ultimate goals of HAE treatment should be to normalize patients' lives. In order to better understand both the patient and physician perspective on HAE and their impression of current treatment options, we conducted our own blinded market research with HAE patients currently on a preventative treatment and also with treatment providers in the U.S. In this research, we learned that HAE imparts a high burden on patients. And despite the fact that all the patients in this survey were already on a preventative treatment, half of the patients we spoke to said that they think about future attacks often or always while the others indicated it was constantly on their minds. They often avoided certain activities like exercise, hobbies and travel, and were worried about missing or unable to maintain a job and had frequent concerns of managing attacks outside the house and the threat of fatal, life-threatening laryngeal attacks. Lastly, the expectation for next-generation effective therapies to reduce the burden of treatment isn't unique to HAE, and there are several other markets that can serve as examples for how the HAE market may evolve. I'll now highlight some of the market research findings in the next 2 slides. This 1 focuses on the patients currently on a preventative treatment and the next 1 focuses on physicians treating HAE patients. We learned that the patients that we spoke to have previously tried 2 to 3 preventative treatments and most often switch for more convenient dosing. All the patients interviewed would be compelled to switch from their current therapy if a new therapy offered similar efficacy with less frequent dosing and 100% or all the patients in this survey said they'd be compelled to switch to a dosing frequency of every 3 months. Our market research with U.S. physicians was equally compelling. We presented a blinded product profile of a monoclonal antibody inhibitor of plasma kallikrein, that has efficacy comparable to twice monthly dosing regimen of lanadelumab but with a dosing regimen of once every 3 months or longer. One question that we asked was on a 7-point scale with 1 being not at all likely to prescribe and 7 being extremely likely to prescribe how likely would they be to prescribe such a profile to their HAE patients. The overall prescriber average in this survey rating on the likelihood to prescribe was a 6.5. So in summary, we found that our insights were consistent with both the patients and prescribers who are not yet fully satisfied with the current treatment options and both continue to look for options that are effective, reduce the burden of treatment and enable patients to normalize their lives. Although the treatment landscape in HAE has multiple competitors on the market and in development, there are several examples in markets like hemophilia, psoriasis and multiple sclerosis, where despite multiple entrants with various dosing regimens, longer-acting effective injectable treatments that ultimately reduce the burden of treatment for patients have garnered significant share as illustrated by the market leaders highlighted in these boxes. Finally, like the markets illustrated on my previous slide, preventative treatments in HAE have evolved in a similar direction with the current market leader being TAKHZYRO, a subcutaneous plasma kallikrein inhibitor injected twice a month or for some patients monthly. The insights from the patients and physicians support our belief that STAR-0215's profile has the potential to be an effective treatment that reduces the burden of treatment for patients and has the potential to play a similar role in HAE as OCREVUS, HEMLIBRA and STELARA have done in multiple sclerosis, hemophilia and psoriasis. I'll now hand the session over to Andy Nichols, who will review the discovery characteristics of STAR-0215 and a summary of the pre-clinical data. Andy?

Many thanks, Andrew. Hello, everyone. So we have heard about the burden of living with HAE and STAR-0215 was designed to provide a solution for the normalization of life for people living with HAE. The goals were to generate a high-potency antibody that could inhibit plasma kallikrein, the same levels as lanadelumab and very importantly, to engineer an antibody with a long circulating half-life with the potential to prevent HAE attacks with dosing once every 3 months or longer. We have seen encouraging preclinical results to date that have demonstrated selective high affinity binding to plasma kallikrein, potent and selective inhibition of plasma kallikrein activity and long circulating half-life and pharmacodynamic activity in nonhuman primates. So we believe that these benefits can translate to a therapy with a long duration of action and infrequent subcutaneous dosing for patients. Today, I will review the discovery of STAR-0215 and some of the preclinical work that we have done to characterize it and understand its properties as a potent, selective and long-acting plasma kallikrein inhibitor. The discovery program started with generation of mouse and the human plasma kallikrein antibodies. In order to increase the likelihood of generating an antibody response, pre kallikrein knockout mice who have never seen plasma kallikrein were immunized with human plasma kallikrein. Out of the over 11,000 hybridomas that were screened, the best 20 that bind to plasma kallikrein were selected and only 1 was found to bind human plasma kallikrein with high affinity compared with pre kallikrein and also to potently inhibit plasma kallikrein activity. This antibody was humanized and further optimized to generate STAR-0213. The Fc domain of STAR-0213 was then modified by an incorporation of so-called YTE mutations, specifically to extend half-life, which generated STAR-0215 and I'll talk more about this later. The potency of STAR-0215 as a plasma kallikrein inhibitor has been characterized in a variety of assays. And in each case, STAR-0215 is at least as potent as lanadelumab when compared side-by-side in the same experiments. In the left-hand panel, you can see that STAR-0215 potently binds to human plasma kallikrein using surface plasma and resonance. And in this format has a 1,000-fold selectivity over pre kallikrein. Using this SBR format, we found that STAR-0215 and lanadelumab do not compete with each other for binding to plasma kallikrein, suggesting that they, in fact, may have different binding sites. The middle panel shows that this high affinity binding for plasma kallikrein translates into high potency to inhibit the enzymatic activity of human plasma kallikrein when using an artificial fluorogenic peptide substrate. STAR-0215 has good cross-species activity and inhibits plasma kallikrein from rat, rabbit, cynomolgus monkey and human equally well. Importantly, STAR-0215 has no activity to inhibit a range of related serine protease and does not bind to any of 6,000 human membrane proteins demonstrating a high level of selectivity for plasma kallikrein. In order to characterize the functional activity of STAR-0215, we used a functionally relevant in vitro biochemical assay to determine the ability of STAR-0215 to inhibit bradykinin production from its physiological substrate, high molecular weight kininogen and it's circulating concentration of 600 nanomolar. Plasma kallikrein concentration used in the assay is 30 nanomole which is in the range that is estimated to be present in plasma during an HAE attack. In other words, we have tried to mimic as closely as we can with biochemistry that occurs during an HAE attack. In this assay, as seen in the far right panel, STAR-0215 potently inhibits plasma kallikrein activity to inhibit the release of bradykinin from high molecular weight kininogen with an IC50 of 15 nanomolar. And the concentration of STAR-0215 required for high-level innovation of plasma kallikrein is similar to the plasma kallikrein concentration used in the assay, 30-nanomole. This is similar to the direct plasma kallikrein activity assays using the fluorogenic substrate as seen in the center panel, where the concentration of STAR-0215 required for high-level inhibition of plasma kallikrein is similar to the plasma kallikrein concentration used in the asset. This suggests that the high affinity of STAR-0215 for plasma kallikrein allows it to be titrated against the level of plasma kallikrein. In other words, if for example, about 80 nanomolar plasma kallikrein is produced during an HAE attack, a singulating level of 80 nanomolar of STAR-0215 would be predicted to produce a high level of plasma kallikrein inhibition. The SPR experiments suggest that STAR-0215 binds to a different site on plasma kallikrein than lanadelumab, and we have explored this further. Here, we can see the results of cross-linking experiments designed to identify the points of close interaction between STAR-0215 and plasma kallikrein, which are shown in purple. You can also see the sites at which lanadelumab closely interacts with plasma kallikrein shown in Cyan and which are different from but which overlap with the sites of interaction between STAR-0215 and plasma kallikrein. We are continuing to explore the binding interactions between STAR-0215 and plasma kallikrein, but these experiments suggest that STAR-0215 binds over a different but overlapping region of plasma kallikrein compared with lanadelumab. A key feature of STAR-0215 and its extended circulating halfway. And I'll spend a little time describing how this was accomplished by taking a vantage of the natural process of antibody recycling. The mechanism by which IgG antibodies have a long circulating half-life compared with most other proteins is well understood and has been exploited and optimized to allow engineering of antibodies specifically for the purpose of modulating half-life. If we follow the cost of proteins and immunoglobulins through their predominant degradation pathway, we can see how IgGs achieve their naturally longer half-life and how we can use that to advantage. We will stop at various points along this pathway to see what is happening. At stop #1, you can see that endothelial cells engulf IgGs from the circulation to form an acidified endosome with a PH in the range of 6 to 6.5. At this acidic pH, the affinity of the Fc domain of the IgG for the so-called neonatal Fc receptor, or FcRn, increases significantly and the IgG in the endo cell binds to FcRn to form an IgG FcRn complex as shown at stop #2. But most proteins do not bind FcRn at this acidic pH and remain free in the endo cell and these proteins that have not bound FcRn are sorted to lysosomes at stop #3. And that leads to degradation by the lysosomal proteases for their final stop at #4. IgGs that are bound FcRn are retained within the endosome and are not sorted into lysosomes for degradation. The endosomes containing intact IgG bound to FcRn, recycle to the cell surface at stop #5, where they are exposed to extracellular blood at a pH of 7.4. IgGs have a very low affinity for FcRn at pH 7.4. And when the endosome recycles to the cell surface and that is exposed to this blood pH, the IgG-FcRn complex disassociates. And at stop #6, the intact IgG gets released back into the circulation. Now this process of IgG recycling is the major determinant of IgG half-life in humans and an increase in pH-dependent FcRn binding will increase IgG half-life. The mechanism of this pH-dependent binding of IgG to FcRn is well understood, and the molecular properties of the Fc region that determine the binding to FcRn have been characterized. A broad range of modifications within the Fc domain have been studied and shown to either increase or decrease FcRn independent binding. We have used the so-called YTE Fc modifications that were first introduced in use by [ Medimeer ] to enhance pH-dependent FcRn binding. Introduction of the YTE modifications into the Fc domain of IgG monoclonal antibodies has been shown to significantly prolong the half-life of these antibodies in both non-human primates and most importantly, in humans. And here we can see 2 examples of the use of this YTE technology. Motavizumab was the first antibody to be compared with and without YTE modifications in humans. You can see that similar to the effect in non-human primates to prolong half-life 3- to fourfold, the YTE modification also increased half-life in humans 3- the fourfold to produce an antibody with a circulating half-life of approximately 80 days. While the development of this specific antibody was not continued, a follow-up antibody, nirsevimab, which has a half-life in adult humans of more than 90 days is now approved in the EU for the prevention of RSV lower respiratory tract disease in newborns and infants during their first RSV season, which can last up to 6 months. Additionally, the component antibodies in every shelf, which in the U.S. has an emergency use authorization for pre-exposure prophylaxis for the prevention of COVID-19 with the allowance for repeat dosing at 6 months also have half-lives in the 80 to 90-day range. Across a range of antibodies with YTE modifications against noncellular targets that are not subjected to target-mediated drug disposition, the half lives in humans most commonly fall in the 80- to 90-day range. And even for those targets with significant target-mediated drug disposition, the introduction of YTE into the Fc domain leads to prolongation of half-life in the 2- to fourfold range. So we utilize this same YTE Fc modification technology in STAR-0215 specifically to extend its circulating half-life. Introduction of the YTE modifications into the Fc domain of STAR-0213 increased pH-dependent FcRn binding about sixfold. This translates into a three to four-fold reduction in the plasma clearance of STAR-0215 in cynomolgus monkeys, which results in a three to four-fold increase of circulating half-life for about 10 days with STAR-0213 to about 34 days with STAR-0215. This extension of half-life in nonhuman primates is in the same range as that's seen with antibodies against noncellular targets that have half-lives in human in the 80 to 90 day range. We have also compared the pharmacokinetics of STAR-0213 and STAR-0215 with lanadelumab in cynomolgus monkeys. Importantly, the half-life of STAR-0215 is also three to four-fold longer than that of lanadelumab, which has the same pharmacokinetic profile as STAR-0213 in non-human primates. Chris will discuss later how we have used this information to model and simulate STAR-0215 may behave in humans and how that compares with the profile of lanadelumab in humans. Next, I want to introduce and describe the biomarker assay that we have developed to study the pharmacodynamic activity of STAR-0215 in non-human primates in which we will use in our clinical trials. As described, the pathologic mediator of HAE is the bradykinin that is produced by the enzymatic cleavage of high molecular weight kininogen by plasma kallikrein. It's very difficult to study bradykinin in vivo because it is rapidly degraded by angiotensin by getting inside. Therefore, we study what's left after bradykinin is released from the high molecular weight kininogen, so-called cleaved high molecular weight kininogen, which is sufficiently stable in plasma for it to be studied. In healthy animals and in healthy humans, the level of plasma kallikrein activity is, in fact, very low and only small amounts of bradykinin and cleaved high molecular weight kininogen are detected. So in this situation, we studied the cleavage of high molecular weight kininogen in plasma after ex vivo activation of plasma kallikrein by Factor XIIa to mimic what happens during in HAE attack. And we measure the amount of the intact and cleaved high molecular weight kininogen using Western blot techniques. In other words, we draw blood samples, generate plasma and factor XIIa and run the samples on a Western blot and determine the amount of intact in cleaved high molecular weight kininogen. And this assay and format are the same as that as used by DX during the development of lanadelumab. And here, we can see an example of how we run this assay. You can see that in samples with no Factor XIIa and no STAR-0215 that there is very little cleaved high molecular weight kininogen. When we add factor XIIa, we can see a clear increase in the cleavage of high molecular weight kininogen, and this is reduced in the presence of STAR-0215. We have used this biomarker assay to study the pharmacodynamic activity of STAR-0215 in cynomolgus monkeys. In this experiment, which was actually part of our GLP toxicology program, we dosed monkeys subcutaneously at either 10, 30 or 100 milligrams per kilogram, 3 times, 14 days apart. In other words, on day 1, 15 and 29 and for the 100-milligram per kilogram group, gave an additional fourth dose 3 months after the third dose. At various time points, we drew blood samples being very careful to minimize the potential activation of the contact pathway to prevent activation of plasma kallikrein. We generated plasma and activated plasma kallikrein by addition of factor XIIa, as I described previously. We measured intact and cleared high molecular weight kininogen using the Western blot technique and determine the degree of privilege of high molecular weight kininogen as an index of plasma kallikrein activity. The basal non-activated cleaved high-molecular-weight kininogen was in the 10% range in these monkeys, and this was increased to 70% to 80% after activation by factor XIIa. This level of factor -- of plasma kallikrein activity remained constant throughout the course of the study up to 125 days in placebo-treated control anoles. Factor XIIa activated high molecular weight kininogen cleavage was significantly reduced by greater than 70% at all doses of STAR-0215 and inhibition of high molecular weight kininogen cleavage was rapid with effects seen within 1 day of the subcutaneous dose administration and with maximal effect within one week. The high dose was able to reduce Factor XIIa activated high molecular weight kininogen cleavage down to the unactivated baseline level. This high level of innovation of high molecular weight kininogen cleavage in the high-dose group was sustained throughout the 84-day dose free period in the extended portion of the study with owning only a minimal return to control. Both of those safely reduced the Factor XIIa activated cleavage of high molecular weight kininogen back to baseline and activated levels. From this, it is clear to see that STAR-0215 produces potent rapid and sustained inhibition of Factor XIIa activated high molecular weight kininogen cleavage in cynomolgus monkeys. And we'll be using this same assay format in our Phase Ia clinical trial that Chris will describe. In summary, we have seen encouraging preclinical results to date that have demonstrated selective high-affinity binding to plasma kallikrein potent and selective inhibition of plasma kallikrein activity and long circulating half-life with potent, rapid and sustained inhibition of factor XIIa activated high-molecular weight kininogen cleavage in non-human primates. And we believe that these benefits can translate to a therapy with a long duration of action and infrequent subcutaneous dosing for the prevention of HAE attacks. And with this, we are aiming to provide patients with a differentiated new therapy using the trusted treatment modality of monoclonal antibodies to prevent attacks in HAE over an extended period of time with the potential of being the most patient-friendly treatment option available for people living with HAE to enable normalization of their life. I will now hand you over to Chris Morabito, our Chief Medical Officer, who will walk you through our planned wonderful program of STAR-0215. Chris?

Thanks, Andy, and hello, everyone. Our goal is to develop a best-in-class therapy for people living with HAE. We have built a clinical development plan that we believe will efficiently establish the potential effectiveness of STAR-0215 in HAE. Here and in subsequent slides, I'll lay out this plan as well as expected landmarks that we believe will provide inflection points with our data that will inform STAR-0215's ability to achieve its target profile. This slide diagrams the key components of this clinical development plan. We're currently in Phase Ia. Our next study is expected to be a proof-of-concept Phase Ib/II trial in people living with HAE, our planned long-term open-label study as well as our planned Phase III pivotal trial will be designed to provide substantial evidence of the safety and efficacy of STAR-0215 and HAE to support registrations in our target markets assuming favorable data in these trials. I am pleased to announce that dosing in the Phase Ia trial is complete. This trial is being conducted in healthy adult subjects at a single site in the U.S. We have enrolled 24 evaluable subjects who have been randomized to receive single subcutaneous administrations of 1 dose of STAR-0215 or placebo. 6 subjects have received STAR-0215 100-milligram, 300-milligram, 600-milligram or placebo subcutaneously and all subjects are now in the follow-up phase. We are following each subject for up to 224 days, which we anticipate as multiple half-lives. We believe that 3-month data will inform on a target profile as data at this time point will tell us whether we're achieving the target thresholds for safety, drug concentration and pharmacodynamic effects at this clinically relevant time point. As I just mentioned, the data obtained from this Phase Ia trial will inform on the target profile of STAR-0215 in HAE, and we expect preliminary data by year-end 2022. The endpoints of this trial are listed on the left. The primary focus of this ongoing trial is safety and tolerability. The secondary endpoints are pharmacokinetics in which we assess blood concentrations over time, and we will be able to calculate important parameters such as half-life, volume of distribution and clearance and pharmacodynamics in which we assess inhibition of kallikrein production via inhibition of plasma kallikrein. We assess pharmacodynamics using a Western blot analysis of fleet, high molecular weight kininogen using similar methodology as was used in lanadelumab's Phase I healthy subject trial and which Andy just reviewed with you. We expect preliminary data by the end of this year. With preliminary data, we expect to be able to determine whether we're on track to achieve STAR-0215's target profile which is described here on the right. Specifically, our primary goals for the preliminary data are that they will show that STAR-0215 may be delivered subcutaneously in small volumes that it has durable activity, that it may be able to be administered once every 3 months or less frequently, and that it's well tolerated and demonstrating a favorable safety profile. While this study is being done in adult healthy subjects, we do expect that we will be able to begin to infer clinical benefit based on anticipated safety, PK and PD results. I've told you now that we have 3 dose levels in the Phase Ia healthy subject trial, 100, 300 and 600 milligrams. Now I want to spend some time discussing how we determine these dose levels. And while doing so, provide some additional information to assist us in interpreting the results that we expect to share by the end of the year. To start, I'll remind you that the mechanism of an HAE attack depends on plasma kallikrein, catalyzing the conversion of high molecular weight kininogen to bradykinin as shown in this cartoon. Local increases in bradykinin causes the swells that characterize HAE attacks, some of which may be lethal to prevent an attack anti-plasma kallikrein concentrations need to be at least equal to and ideally greater than plasma kallikrein concentrations. We can infer target minimum concentration or Cmin needed to prevent attacks by looking at other plasma kallikrein inhibitors in HAE. Ecallantide, a potent plasma kallikrein inhibitor is clinically affected in managing acute attacks at concentrations of 80 nanomolar. Lanadelumab, another plasma kallikrein inhibitor is effective at preventing attacks at Cmin values greater than 67 nanomolar. So just as Andy introduced to you a few minutes ago, we'll set the target in healthy subjects to be a 3-month Cmin of more than 80 nanomolar or 12 micrograms per mil. That is to say that we hypothesized that STAR-0215 may be clinically effective for at least 3 months at the minimum concentration of drug at 3 months is greater than 12 micrograms per mil. The Phase Ia trial will show us the STAR-0215 can achieve this target. Finally, I'll point out that multiple doses of STAR-0215 may be required to achieve rapid and high steady-state concentrations to induce clinical efficacy. On the next slides, I'll show you simulated data from our model which explain this more. Here, we're showing simulations of STAR-0215 concentration curves over time developed from physiologically-based quantitative systems pharmacology model. This model is not yet modified to include human PK data as those data won't be available until later this year. On the left, you'll find concentration curves after simulated 30, 100, 300 and 600-milligram subcutaneous infusions in humans using a target threshold of 12 micrograms per mil, the 3-month Cmin level, we predict will have meaningful clinical benefit in humans. Doses of 100 milligrams or greater maybe expected to be clinically important. So we chose 100, 300 and 600 milligrams as a single dose levels for the Phase Ia trial that's currently ongoing in order to ascertain safety, PK and PD at these levels. On the right, you see a simulation of a multiple dose regimen in which a loading dose of 300 milligrams at day 0 is given to boost rapidly STAR-0215 levels to potentially therapeutic concentrations followed by a maintenance dose of 150 milligrams given every 3 months. These data suggest that this regimen may maintain concentrations above the Cmin threshold of 12 micrograms per ml. Data from the Phase Ia trial in healthy subjects will be able to tell us whether this kind of regimen has the potential to achieve the desired rapid onset and maintenance effects of STAR-0215 in people with HAE. Moving to the next slide. I'll compare the simulator profile of STAR-0215 on the left to lanadelumab's profile on the right defined by its pop PK model. On the left, as we just discussed, a loading dose followed by a maintenance dose every 3 months has the potential to rapidly cover plasma kallikrein while it takes up to 5 administrations of lanadelumab to achieve steady state to inhibit the enzyme. Also noteworthy is the potential burden to patients. STAR-0215 may be effective with 4 subcutaneous administrations per year, while the majority of patients receiving lanadelumab will be reminded of their disease more than 25 times per year, taking this medicine every 2 weeks. Further, we hypothesized that STAR-0215's profile in which there are durable high concentrations of anti-plasma kallikrein antibody has the potential to result in longer periods of time in which patients are attack-free and maybe a higher proportion of patients who are attack-free. Now I'll discuss interpretations of the expected year-end pharmacodynamic data. Measuring cleaved high molecular weight kininogen informs the pharmacodynamic activity of plasma kallikrein inhibit inhibition and a potential clinical benefit. Cleaved high molecular weight kininogen is the primary pharmacodynamic biomarker in our Phase I trial. Here you see data from lanadelumab's Phase Ia healthy subject trial, the highest dose level tested reduced clean high molecular weight kininogen to less than 30% or by approximately 50% from baseline at day 5, which held to day 28 after single dose administrations. This lanadelumab dose of 3 milligrams per kilo in a population with a mean weight of 83 kilos is just on average, slightly less than the current recommended clinical dose of 300 milligrams, which has demonstrated clinical effectiveness. The ongoing STAR-0215 Phase I trial in healthy subjects is expected to determine whether STAR-0215 actively engages and inhibits the plasma kallikrein target, assessed by changes in cleaved high molecular weight kininogen, demonstrating similar changes in cleaved high molecular weight kininogen in STAR-0215 Phase I trial as those seen in lanadelumab's Phase I healthy subject trial would support the potential for clinical effect. As I said earlier, it's possible that a multiple dose regimen may be effective and potentially selected for future clinical trials. And we look forward to sharing preliminary results with you by the end of this year. Moving on now to planned clinical development. I will introduce to you our next planned trial of Phase Ib/II proof-of-concept trial in patients called ALPHA-STAR for Astria long-acting prophylaxis for HAE STAR-0215. We are well on our way towards initiating this planned trial, which we aim to start in Q1 2023. As stated, this would be a proof-of-concept trial in which we'd ask the question, does STAR-0215 have the potential to safely and effectively prevent HAE attacks. This would be a global trial with multiple sites. We plan to test a single dose and multiple dose regimen in this trial. We believe that a small sample size will be sufficient in order to give us confidence in potential effectiveness. And importantly, each qualifying participant would receive at least 1 dose of STAR-0215 and participants would be permitted to roll into a long-term open-label study. As a proof-of-concept trial, our goals are to see a safe, durable activity compatible with robust clinical benefit, subcutaneous administration that is patient-friendly and results that will ultimately inform the dose selection for our pivotal trial. ALPHA-STAR is expected to be an open-label, single and multiple dose Phase Ib/II POC trial in HAE. We plan to have 2 cohorts. The first cohort would assess a single dose of STAR-0215 over 6 months, the second cohort starting slightly after the first would assess a multiple dose regimen of STAR-0215 over a total of 9 months. We are planning for each treatment period to be preceded by a rigorous run-in period. After screening, consenting participants would be followed for 8 weeks to assess a true baseline of HAE attack frequency as well as establish a baseline profile for safety comparisons. This run-in period has the potential to provide placebo-controlled like data for both safety and clinical effects changes after STAR-0215 administration. In Cohort 1, each qualifying participant who has completed the running period successfully would receive a single dose of STAR-0215. In Cohort 2, qualifying subjects will receive a loading dose followed 3 months later by maintenance dose. All subjects will be followed for 6 months after the last dose received. This time period would be expected to provide important information about the durability of the effect of STAR-0215 and will help us select dose levels and dose frequencies for future trials. The final analysis is being planned for 6 months after the maintenance dose of STAR-0215 in Cohort 2. There would be formal interim analysis along the way to help us understand whether any modifications to the trial may be needed including the potential to add additional cohorts and to trigger the potential start of the Phase III trial, assuming positive data. Qualifying participants would have the opportunity to participate in our long-term open-label study as well once that is opened. On this next slide, we recognize that a very important element of success for this trial is enrollment, and we are proactively taking steps to mitigate this risk and its potential impact. While enrollment rates in HAE clinical trials do not appear to be slowing down, success of this trial depends on our unremitting focus on execution. Here, I'll outline the steps we are taking to address and actively mitigate this risk. First, as you can see in the top circle, we believe that our planned trial design would reduce protocol burden. As an open-label trial, we have designed the trial with the goal of eliminating the access to investigational drug challenge. There will be access to investigational drug for all qualifying participants. Our planned trial design also minimizes in-person assessments. Patients around the world typically travel to the specialty center for their care, which are potential trial sites and we expect that fewer in-person visits will have a meaningful impact on trial participants burden. Second, moving clockwise, we are aiming to optimize site activations. We are being smart about site selections, carefully studying HAE prevalence around sites, market availability and access to approved drugs for HAE and site's previous experiences in HAE trials. Further, we are planning to boost site activations to facilitate rapid enrollment engaging our launch mode for this trial that we expect will result in a group of sites that are activated with potential participants in queue for early enrollment into the first cohort. Third and potentially most important, we are engaging actively with our communities. The HAE community is fortunate to have a strong unified advocacy support mechanism and the patient and provider communities have a strong history of promoting research aimed at improving the health of the HAE community, as our trial is. We are planning to activate trial advocacy across patient, partner and caregiver communities in which we aim to develop trust. We are working hard on these activities now well before the trial is set to start so that the figurative enrollment sweet spot is as large as possible. Finally, I'll conclude with a glimpse of planned future trials that would support registration. We are planning a long-term open-label study that we expect would be a Phase II trial without a placebo-control. The aim of this trial will be to assess long-term safety and clinical effects of STAR-0215 in HAE, HAE subjects who have consented to participate in a clinical trial of STAR-0215 would have the potential to participate in this trial. We are just beginning to plan out the potential Phase III pivotal trial here after consultations with the relevant health authorities and assuming favorable data in the proof-of-concept trial, we anticipate a randomized, blinded, placebo-controlled global trial to assess the efficacy and safety of STAR-0215 in HAE. As we think about the future, we are excited about the potential for STAR-0215 to provide long-acting effective attack prevention for people living with HAE. At Astria, we are deeply committed to improving the health and lives of the people we serve, the people living with HAE and their care partners. Our goal is to reduce disease burden and treatment burden to enable the HAE community to spend substantially less time thinking about and managing their disease. I'll now conclude and open up for discussion and questions. And back to you, operator.

[Operator Instructions] And our first question will come from Joe Pantginis at H.C. Wainright.

Thanks for the details today and all the information and looking forward to the upcoming data. So my first question is a quick one, just starting at the back end of your comments. With regard to the upcoming ALPHA-STAR study, what is your current communication strategy around the interim looks? Or is it just going to be internal?

Chris, do you want to take this question and maybe refer to the preliminary data we'll be sharing this year and how we're thinking about ALPHA-STAR?

Sure. So for ALPHA-STAR itself, we have built in some interim analysis like we talked about just a second ago, and that's primarily for helping us understand how to potentially improve the trial or to make some important business decisions. We haven't yet communicated how we intend to share those results. And certainly, as we get closer to those key inflections we'll be more -- we'll be able to share more information about that. We are looking forward to sharing additional information at the end of this year for the Phase Ia trial that will be preliminary data that should inform on the drug's target profile.

Got it. And I appreciate that. And then my next question, it's really a two-pronged question, and I think it's most applicable to Dr. Riedl, and I appreciate all the color that he provided today. First, I guess, overall, when you're looking at the target -- potential target profile of 0215, the first part is obviously, with all the work that we've been doing and everything that's been shared today, convenience is the key thing here that patients are looking for. So I guess I'd ask it this way. When you look at convenience versus efficacy, would -- could you benchmark right now if the drug moves forward that it require in your hands, for example, the same efficacy as lana? Or is there room for potentially less efficacy with the potentially significant increase in convenience. That's part one.

Yes, it's a good question, and it's also a difficult question to answer because it's so variable on each patient and what their -- what's important to them. My experience in discussing this with a lot of patients because we have this discussion with the current therapies is that they will give up a little bit of efficacy for convenience or tolerability, but at the end of the day, it still needs to be effective enough for them. And so my view is that probably a therapy like this needs to come in close to what we're seeing with lanadelumab as far as efficacy. But I do think if it's dosed truly with the target of every 3 months or less, they probably -- patients -- many patients will probably give up a little bit of efficacy to achieve that dosing interval. So I'm sort of hedging, but that's because it's a really hard thing to discuss. It's going to differ from patient to patient.

No, absolutely. That's a fair answer. And you actually answered the part 2 of my questions. So I'll just ask this. And this is really forward-looking with regard to technology. How do you view gene therapy's potential currently because, look, I mean, 0215, if successful, has a very robust potential profile here with dosing. So with regard to gene therapy, do you view it as a threat, another option for patients, the overall promise and risk perceptions around it?

Yes. I think for now, I would view it as another potential option. I mean, listen, those of us that do the research and see the patients would love to have a single treatment that would have a very long durable effect. And I won't say cure because -- we don't know if that's what gene therapy can do at this point. But I think in concept gene therapy is very attractive. That being said, there's a lot that we don't know about it in this -- in general and also in HAE specifically. And so I think I think those studies are moving ahead very cautiously, and I think we have to have a better understanding of the risk profile of that sort of approach versus a more well-known approach of monoclonals or some of the oral medicines, targeted medicines. So I guess I'm very cautiously optimistic about gene therapy, but the key word there is caution. I think we have a lot to learn yet about how that's going to work.

Absolutely. I appreciate that. And just quickly, I mean, with the upcoming data, we don't have the data yet, obviously, but there are a lot of eyes on it. How would you, as a physician interpret healthy volunteer PK and PD data, specifically saying you want to see a certain level of kallikrein inhibition and your confidence how that would then translate to HAE patients specifically?

Yes. I guess I would view it as there's a track record or a history here, right? I mean we know this is a validated target based on the other treatments that have been shown effective. So generally, from a past experience and other groups having done this sort of work, I feel pretty confident that, that will translate the Phase I will translate to being a very good candidate or for being successful in treating patients again, mainly because there's a track record of sort of using this approach. So I think we can have some confidence in what that data shows.

The next question comes from Suji Jeong from Jefferies.

Can you hear me okay?

We can.

So I have a couple of questions about the use of 80 nanomolar for the Cmin bar. My understanding was that the IC90 concentration of STAR-0215 is 10x lower than that of TAKHZYRO. And I was just wondering why -- first of all, how you arrived at the Cmin 80-nanomolar for STAR-0215? And why do you think -- why is it 80-nanomolar? Why is it higher than assuming that level that you have on the slide for TAKHZYRO which is 67?

Chris, do you want to take this question and perhaps Andy add on.

Yes. Great. So I'll get things start and Andy's help with understanding potency would also be appreciated. So I try to explain it, and I'll try once more and see if I can make it a bit more clear. What we're trying to do with STAR-0215 is meet or beat the concentration of kallikrein in plasma because we want to be able to prevent that kallikrein from turning high molecular weight kininogen into bradykinin. Getting our hands on data to inform the concentration of Kallikrein in HAE is not easy. There have been a few studies that have looked and tried to give us a sense about what that concentration could be. We have now turned our attention to other analogs in the space, other plasma kallikrein inhibitors to give us a sense about what kinds of concentrations would be effective in managing to allow us to infer what those concentrations of kallikrein are in people with an attack. So the first analog is a ecallantide, which is a potent plasma kallikrein inhibitor that's used to treat an acute attack. And the mean concentration of ecallantide after 30 milligrams delivered subcutaneously is 80-nanomolar and it's effective in reducing attacks. So that data point by itself says that 80 is about the concentration of kallikrein that is in plasma that needs to be inhibited. So that's where that first number 80 comes from. The second analog we looked at was lanadelumab, which has a substantial amount of data in the public domain that essentially show that when you have a Cmin concentration of at least 67 nanomolar you're effectively preventing HAE attacks. So that tells us that we have to have our drug concentrations over that 67 nanomolar threshold in order to meet or beat the circulating plasma kallikrein concentrations in people who have HAE in order to prevent attacks. So that's where the 80 has come from, and that's our current bar for the PK in the Phase I trial. And Andy, do you want to get to that potency topic?

Yes. So it's a great question because it's a little bit difficult to understand sometimes. But what the goal of the program really was, was to come up with a plasma kallikrein inhibitor that was at least as potent as lanadelumab. And we've clearly accomplished that because in all of our assays that we've run, we're at least as potent as and sometimes more potent than lanadelumab the most potent plasma kallikrein inhibitor in vitro biochemical assays is ecallantide. That has an affinity of 25 picomolar -- but we still need 80-nanomolar to be effective in stopping progression of an HAE attack. Why is that? That's because you need at least the same amount of drug as there is plasma kallikrein. And if you have a high-enough affinity for plasma kallikrein, and we believe that we do, then you need about that level of drug as you have plasma kallikrein. And the amount of plasma kallikrein that is present during an HAE attack, we don't know what the number is precisely, but we can get it from a variety of different means. One is there's been some measures of it and estimated to be in the 30 to 100 nanomolar range. The fact that lanadelumab has shown efficacy when a Cmin of 67 nanomolar. And ecallantide has efficacy to prevent further progression of an HAE attack with a concentration of 80-nanomolar suggests that as long as we can achieve 80-nanomolar and with the high affinity and high potency to inhibit plasma kallikrein, we should be inhibiting plasma kallikrein at least to the same level as lanadelumab and ecallantide can do.

I see. I think I'm following it now. And another question is -- when you present the Western blot data for the ex vivo assay , will you be having active control arm for the assay so that we can compare head-to-head against TAKHZYRO?

Andy, do you want to take this one?

We will not be including an active control arm. No, we'll be looking at STAR-0215.

Okay. And lastly, for the ALPHA-STAR trial design, there is an 8-week run-in period. So I'm assuming the patients will be coming off other prophylactic treatment during the -- before 8-week run in. Do you think the 8-week would be enough for the patients for TAKHZYRO, perhaps, to be clear from the plasma completely.

So yes, just to clarify that nuance. So it will be 8 weeks before the trial starts that we follow these patients. And during that time, patients will have already been washed off. So the wash off occurs well before the start of the other run-in period. So we will be -- if patients who are on lanadelumab or any other preventative therapy participate or want to participate in the trial, we have specified that it should be prophylaxis medicine free by the time to start that run-in period.

How long does the washup period have to be?

Typically, it's about 5 half-lives for each medicine.

I see.

[Operator Instructions] So the next question will come from Laura Chico at Wedbush.

I guess I have 1 for Dr. Riedl, and this relates kind of to the patients that you're currently managing with respect to your current patient load, how often are patients changing their long-term prophylaxis regimen. And I'm guessing what proportion of those patients are on a long-term prophylaxis regimen?

Sure. So at the moment, we have about 2/3, 65% to 70% of patients on a long-term prophylactic treatment. In terms of -- and I should say we've seen gradual slow growth of that over the years, again, as the additional options have come along. So we're definitely using it more often than in the past. In terms of switching therapies, it's not that common that people switch. I think every time that there's a new option that's FDA approved, certainly, there's some movement, and that's where we've added some patients that weren't on long-term prophylaxis to a newly available agent. Generally speaking though, if patients have done well on some of the newer treatments, for instance, lanadelumab or subq C1 inhibitor, there is a subset that will move to something different. Of course, it depends on the differences between those therapies. But I will say the biggest thing has been efficacy, honestly. I'm sure people care about convenience and tolerability. And so dosing schedules do make a difference. But there is some hesitancy if a patient is doing really well on a treatment to go to a treatment that might have less efficacy based on the study data. So that's why I think I said a couple of times, efficacy always kind of carries the day. There is some wiggle room based on how a drug is given and how tolerable it is and what side effects there are. But patients care a lot about how well this is going to work. And so while they will move, it's not -- we don't see huge shifts from 1 drug to another generally it's sort of a slower process than that, if that makes sense.

The next question comes from Hartaj Singh at OpCo.

And a really, really comprehensive presentation. Thank you so much. I had 1 question just based on kind of the regulatory feedback, everything that you've seen in this area where some other drugs have been approved recently, the lanadelumab approval. You've got a biomarker assay. You're going to do a Phase I and get a Phase Ib/II with some interims in there and ALPHA-STAR. How possible is it that you could, using the biomarker assay, get to sort of an accelerated approval kind of pathway. Would you have to go through a full Phase III? Or could there be a combination of biomarker assays using that plus some size effect on efficacy maybe on dosing duration 3 months or longer. Could there be some combination of these that could lead you to an accelerated trial approval or do you see a more sort of regular pathway for approval going forward? I know it's early. I just want to get any thoughts.

Thanks, Hartaj. Chris, do you want to take this one?

Yes, I'd be happy to. It's a wonderful side. It's certainly something that we've contemplated ourselves. We haven't had the conversation with the regulators yet with any of them actually about this particular idea, but it's something that we have internally discussed. The challenge, of course, is being able to demonstrate that this biomarker is a surrogate for clinical effect. We know that it does -- it is associated with clinical effects that surrogacy bar is hard, it's hard to achieve. So we're currently thinking about what is it that we need to do to establish that surrogacy before we bring this to the regulators. But absolutely an interesting idea. And of course, we're all looking for ways to accelerate the regulatory path, so we get this medicine closer to patients as fast as we can.

And the next question comes from Sam Slutsky at LifeSci Capital.

Just for Dr. Riedl, given the profile of STAR-0215, can you just discuss the expected interest from patients and enrolling in the upcoming clinical studies with the drug as well as just overall typical ease or difficulty of enrolling HAE studies in today's environment?

Sure. I think that, as I think was mentioned earlier, we have continued to enroll in clinical trials up until now. And even though there has been considerable advances, we're still seeing interest amongst patients as long as there's -- it's pushing the field forward in some meaningful way, and we've talked a lot about that ease of use, tolerability, efficacy. These are all things that patients are interested in improving. So I think it has become a bit more challenging, although we've continued to see enrollments tick along. I've spent a lot of time talking with multiple industry folks about how to make the clinical trials as palatable as possible to patients because they're very savvy. They know what questions to ask. They know a lot about clinical study design at this point having been around the field for a number of years. So I think you heard in their design some things that try to make this as efficient as possible and some of the potential benefits downstream for patients that agree to be in the study. And -- of course, you have to generate the data that the regulators want to see so you can't compromise that. But I'm optimistic. I think we have to work a little harder to get people into studies now, but there continues to be great interest amongst the community. So I think this is achievable assuming that Astria sort of comes through with a lot of things that they outlined to engage the community and make sure that they generate interest and make the study design as user-friendly as possible.

And the last question will come from Michael Higgins at Ladenburg.

Appreciate the questions. I thank the host for the call, and thanks again for participating in our conference yesterday. So as possible, we had some prep for today's call. So I appreciate that. A lot of good questions asked and certainly some focus on the words of both dose frequency and efficacy as it relates to adoption. I just want to poke it a bit further on that. Are there specific thresholds in the data that we'll see that you'll be looking forward from the Phase I that will give you some confidence in the efficacy that is on track with lanadelumab?

Yes. Maybe I'll start and have Chris chime in. So I think in terms of the Phase Ia, what we'll certainly be looking at is the half-life of STAR-0215 and the drug levels achieved at that time form where we are aiming for, and that's to support in every 3-month dosing. We'll also be looking for reduction in the biomarker assay comparable to what was observed with lanadelumab in their Phase Ia healthy volunteer study as well. And Chris, I don't know if you want to add anything to that?

Yes. I think just the 1 piece that probably is obvious, which is just that it's well tolerated. So I think the key here is to get the drug levels as high as we can for as long as we can right now, that could be limited only by tolerability. So that's certainly something that we're keen to look at. But as Jill outlined all the other parameters perfectly well.

Appreciate it, look forward to that.

I'll now hand the call over to Andrea Matthews at Astria for any questions that came in over the webcast.

Thanks. I appreciate that we're getting a bit long on time here, so we'll just limit this to a couple. One of the ones that came in here, it probably goes to Chris, what are you seeing for initial data from the Phase Ia trial and how's the data?

Yes. So first, we're not routinely continuously looking at the Phase Ia data as they come in, but we have looked at them for helping us understand how to dose or determine dose levels for the upcoming Phase Ib/II trial. So we have seen very early data from that trial to help us think about the design and the dose frequency for the Phase Ib/II. The data are consistent with our expectations. We're not seeing surprises there, which is fortunate. And I will say that we're not looking again at data until year-end, with the exception of safety, which we continuously monitor.

And then we'll do just 1 more, and then I'll pass it back to Jill for closing remarks. What data do you expect to have at year-end? How many cohorts and through what time point?

Sure. I'll take that as well. Thank you. So we have completely enrolled the trial. Everyone has received drug. We're just in the follow-up phase, and I outlined that a little bit ago. which is all very good news. And we're certainly on track to be able to provide what we think will be a comprehensive set of data by the end of the year. We expect to have safety, PK/PD data by year-end for all 3 cohorts and 3-month data from the initial cohorts that we have enrolled. So those data will help us understand whether we have a well-tolerated profile that looks like it has a favorable safety profile so far that the PK is what we expect that it has a long half-life that it's compatible with 3 months or less frequent dosing demonstrating its durability and that this can be delivered in small volumes subcutaneously, which is all consistent with our target profile.

Jill, I'll pass it over to you.

Thanks, Andrea. We've made exciting progress over the past year with bringing STAR-0215 through completion of an IND filing and into the clinic. And as Chris had gone through earlier, all subjects have been dosed in our Phase Ia trial of STAR-0215 and we see this trial as an opportunity to inform on the differentiated profile of STAR-0215 as a potential best-in-class treatment for HAE. This trial, again, is monitoring safety, tolerability, and we anticipate the results will be informative in terms of pharmacological activity in the half-life of STAR-0215. And again, preliminary results are anticipated at year-end this year. Thank you very much for joining us today. We look forward to keeping you all updated as we make progress on STAR-0215's clinical development. Thank you.