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

Good day, and welcome to the Astria Therapeutics Phase Ia results conference call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker, Ms. Andrea Matthews, Senior Vice President of Corporate Affairs. Please go ahead.

Thank you. Welcome to today's Astria Therapeutics' STAR-0215 Phase Ia results conference call. With me today are Jill Milne, Chief Executive Officer; Christopher Morabito, Chief Medical Officer; Andy Nichols, Chief Scientific Officer; Andrew Komjathy, Chief Commercial Officer; and Noah Clauser, Chief Financial Officer. We issued a press release this morning summarizing the results from our Phase Ia trial with the STAR-0215 program, which is available on our website. We are also using slides during today's call that are available within the webcast and on the Events & Presentations section of our website. I would like to note that during today's event, as mentioned on Slide 2, we will make forward-looking statements related to our business based on current and future expectations. Actual results may differ materially from those indicated by those statements as a result of varieties of risks and uncertainties, including those discussed in our most recent Form 10-K and our subsequent SEC filings. Such statements represent our judgment as of today, and we undertake no obligation to publicly update any forward-looking statements except as required by law. I will now pass the call over to Jill, Chief Executive Officer. Jill?

Thank you, everyone, for joining us today. Moving on to Slide 3. We are excited to share the preliminary results from our Phase Ia trial of STAR-0215 in healthy subjects. As a reminder, we see STAR-0215 as a unique and exciting opportunity in the hereditary angioedema space. Importantly, STAR-0215 targets an already clinically validated mechanism, and it does so with a trusted modality in the form of a monoclonal antibody. Our goal with STAR-0215 has been to not only address disease burden in patients, but also to address treatment burden. We want people living with HAE to be able to focus on what is important to them and not to have to focus on their disease or treating their disease. We believe based on the results we will share today, that STAR-0215 has the potential to be a best-in-class agent that provides long duration of effect and is one step closer to achieving our vision for the program and for patients. With these results, we are thrilled that STAR-0215 has shown early proof of concept for its target profile, a long-acting preventative therapy for hereditary angioedema, a best-in-class PK profile and dosing once every 3 months or less frequently. There are 3 important elements to the positive preliminary results from the Phase Ia trial that we will walk through today. First, STAR-0215 was well tolerated and associated with a favorable safety profile. Second, STAR-0215 showed rapid and sustained drug levels with a half-life of up to 110 days. And third, we have demonstrated target engagement with durable plasma kallikrein inhibition seen through 3 months following a single dose of STAR-0215. We are thrilled that these preliminary results support the desired profile for STAR-0215 and answer the key questions that enable us to progress our clinical development to HAE patients. Activities are underway on the Phase Ib/II ALPHA-STAR trial, which we expect to initiate in Q1. The trial will evaluate safety, tolerability, HAE attack rate, PK, PD and quality of life in HAE patients after single or multiple doses of STAR-0215. This trial could provide proof of concept in HAE patients and initial results are expected in mid-2024. Having achieved the desired results supporting once every 3 months dosing, we believe that the data suggests that it may be also possible to dose less frequently. Therefore, we are planning to evaluate the potential for 6-month dosing with STAR-0215 with additional cohorts in this Phase Ia trial. We expect to have the results from these cohorts in Q4 of 2023. At Astria, our mission is to bring hope with life-changing therapies for patients with rare and niche allergic and immunological diseases. Thank you to our team for their drive and dedication to progress this program with the aim of improving the lives of those impacted by hereditary angioedema. On the next slide, Slide 4, for anyone who is not familiar with hereditary angioedema, or HAE, I will provide a brief background. HAE is a rare life-threatening and life-changing disease, characterized by severe unpredictable, painful and sometimes life-threatening edema in skin, the abdomen and the airway. Patients with HAE live in fear of having an attack, an attack that could be immensely painful or leave them disfigured for several days or worse, an attack that could be fatal. There are approximately 8,000 people affected in the United States and approximately 15,000 people affected in the EU and the average age of onset is 11 years old. The standard of care for HAE has evolved to include 2 types of therapies, on-demand therapies that are taken acutely in response to an attack to limit attack duration and severity, and preventative therapies that are taken chronically to prevent attacks from occurring in the first place. Our vision for STAR-0215 is as a preventative therapy to help prevent attacks from occurring. Turning to Slide 5. STAR-0215 is a potent and long-acting inhibitor of plasma kallikrein, an established target to prevent attacks in HAE. In a healthy individual, the mild stress of normal daily activities, such as pressure from holding an object can trigger the contact activation system, which results in the activation of factor XII, generating factor XIIa and the subsequent production of plasma kallikrein for pre-kallikrein. However, in healthy individuals, this system is kept in check by a protein called C1 inhibitor, which blocks the function of factor XIIa and plasma kallikrein. And as a result, very little active plasma kallikrein is produced. And hence, there is no consequence of this tissue stress. In contrast, in people with HAE, C1 inhibitor is either absent, present at low levels, or defective. And thus, there is no break for factor XIIa and the plasma kallikrein. As a result, we get a runaway contact activation pathway and plasma kallikrein is produced at high levels and is active to cleave high molecular weight kininogen to produce bradykinin, which leads to pathological edema and pain. With STAR-0215, our goal is to inhibit the pathological activity of plasma kallikrein, thereby preventing HAE attacks from occurring in the first place. Moving on to Slide 6. STAR-0215 was designed with a vision of normalizing the lives of people living with HAE. The goals of our program were twofold. First, to generate a high-potency antibody that could inhibit plasma kallikrein to the same level as lanadelumab, the market-leading approved monoclonal antibody inhibitor plasma kallikrein. And second, to engineer an antibody with a long circulating half-life with the potential to prevent HAE attacks with dosing once every 3 months or less frequently. STAR-0215 has shown selective, high-affinity binding to plasma kallikrein and potent and selective inhibition of plasma kallikrein activity. STAR-0215 includes YTE modifications in the Fc domain to extend its half-life. The high concentration in our formulation enables patient-friendly subcutaneous dosing and STAR-0215 is also formulated to reduce pain for patients. On Slide 7, you can see that this profile was supported by preclinical studies, the results of which we have presented previously. Briefly, we have demonstrated that in a physiologically relevant in vitro assay that is set up to mimic what occurs in an HAE attack, STAR-0215 inhibited plasma kallikrein at least as potently as lanadelumab. When we looked at PK in non-human primates, we also saw the STAR-0215 half-life was more than 30 days, which is about 3x longer than lanadelumab in non-human primates. These results were compelling and supported our vision for STAR-0215 as a potential long-acting therapy for HAE and importantly, led to the decision to advance STAR-0215 into clinical development. We're excited to share today the results of our first clinical trial with STAR-0215 in healthy adult subjects. I will now hand the call over to Chris Morabito, our Chief Medical Officer, to review the Phase Ia trial design and results. Chris?

Thank you, Jill. Let's start with Slide 8. We are pleased to report preliminary data from our ongoing Phase Ia trial of STAR-0215 This is a randomized, double-blind, placebo-controlled trial of single ascending subcutaneous doses in healthy adult subjects. There are 3 dose cohorts and each has 8 subjects, 6 on STAR-0215 and 2 on placebo. The doses for this trial were selected based on the model we built from non-human primate data. In this model, the dose level of 100, 300 and 600 milligrams were predicted to have potential for clinical benefit. Today, we are providing up-to-date accumulated preliminary data regarding safety, PK and PD. For safety, we have 84 days or 3 months of data from all 3 cohorts. For PK and PD, we have data for up to 84 days in the 100-milligram and 300-milligram cohorts, and up to 56 days for 2 months in the 600-milligram cohort. Turning to the next slide. We believe that the preliminary data that we are showing today strongly inform the potential of STAR-0215 to be a safe and effective long-acting preventative treatment for HAE that is to define early proof of concept. In this Phase I trial, we have asked 3 important questions. First, the STAR-0215 have a favorable safety profile. Second, our concentrations of STAR-0215 sustained at levels consistent with potential clinical benefits in people with HAE. And finally, the STAR-0215 demonstrates target engagement assessed by reductions in cleaved high molecular weight kininogen. In the upcoming slides, I'll review these data with you and ultimately confirm that we have demonstrated all 3 of these aspects. Moving on to Slide 11. The demographic characteristics of the healthy subject population are shown on this slide. There is a near equal distribution by gender and a predominance of African-Americans in the total population. The mean weight of subjects in this trial is 86 kilos, slightly higher in cohort 1 and lighter in cohort 3. There are 9 subjects listed in cohort 1. In this cohort, one subject did not receive a full dose due to an administration error. Ultimately, this subject was replaced, yet due to the preliminary nature of this report, this subject's safety, PK and PD data are currently included. All right. To start, let's focus on safety and tolerability on Slide 12. To date, these preliminary data suggests that STAR-0215 is well tolerated and has a favorable safety profile. In total, there were 8 subjects with related treatment-emergent adverse events. All treatment-emergent adverse events were mild and resolved. There were no moderate, severe or serious adverse events. There were 6 subjects with injection site reactions. The most common injection site reaction was injection site redness. There were no reports of injection-associated pain. As noted, there were all -- these were all mild and resolved without sequela. For perspective, the most commonly reported adverse reactions associated with lanadelumab or injection site reactions, most commonly pain, upper respiratory tract infection and headache. More than half of lanadelumab-treated subjects reported injection site reactions with administrations. On Slide 13 now, let's go on to the PK data, which reveal that STAR-0215 has the best-in-class PK profile. In the left figure, you see 2 concentration curves comparing similar doses of STAR-0215 and lanadelumab, both after single subcutaneous doses in healthy adult subjects. 3 milligrams per kilo lanadelumab is the highest dose tested in healthy adult subjects and is approximately 250 milligrams. These data show that the estimated half-life of STAR-0215 is up to 110 days, over 5x longer than lanadelumab. You can see that there is rapid achievement of maximum concentration similar to lanadelumab. Also note that there are sustained concentrations at levels consistent with clinical benefits, which is durable. Based on this PK profile, we believe that we may be able to find a regimen for STAR-0215 that could allow for every 6-month administration. To assess this, we are planning to add cohorts to the Phase Ia trial. Shown on Slide 14 on the available concentration over time data for all 3 dose cohorts, 100 through 600 milligrams given one time subcutaneously. Note that the profiles show rapid and sustained concentrations over time after a single subcutaneous doses and that the concentrations are proportional to dose. You can see visually that the elimination phase is long. This long elimination phasing caused by the YTE modification, which is designed to prolong half-life by up to 100 days by slowing down drug clearance. The 300 and 600-milligram profile shows durable concentrations at levels consistent with clinical benefits for at least 3 months. Moving to Slide 15. While we may -- while we have not determined the go-forward dose regimen, we have simulated at least 1 possible clinical dose program using these data from the healthy adult trial. These results show the potential for clinical benefit within treatment dosing. Here you see the potential clinical PK profile after a single 600-milligram loading dose and then 300 milligrams given every 3 months. The 600-milligram loading dose would be used not only to boost initial anti-plasma kallikrein antibody levels, but also to accelerate the achievement of steady state minimum concentrations. The concentration threshold associated with clinical benefit is 80 nanomolar. This target threshold comes from clinical data of plasma kallikrein inhibitors in patients. As shown in this simulation, the concentrations of STAR-0215 always remain above 80 nanomolar; there were no excursions near or below that threshold. I'll now pass it on to Chief Scientific Officer, Andy Nichols, who will now review the pharmacodynamic results. Andy?

Thank you, Chris. So turning to Slide 16. We assessed the pharmacodynamic activity of STAR-0215 by measuring the functional inhibition of plasma kallikrein using an assay similar to the assay used by Dyax in their Phase I trial of lanadelumab in healthy volunteers and which allows them to predict doses that would be effective in reducing HAE attacks. As Jill talked about earlier, in healthy adult subjects, plasma kallikrein levels are very low. So in order to mimic what happens during an HAE attack, we stimulate the production of kallikrein ex vivo by adding factor XIIa to samples taken from the subjects before and various time points after dosing. The plasma kallikrein that is produced in cleaved high molecular weight kininogen, and we use the Western blot technique to measure this cleavage with high molecular weight kininogen. As a reminder, the panel on the right-hand side shows that using this technique, lanadelumab at 3 milligrams per kilogram or approximately 250 milligrams produced about a 50% reduction in this factor XIIa activated cleavage of high molecular weight kininogen in healthy volunteers. On the next slide, we show that STAR-0215 inhibited plasma kallikrein and produced a sustained 40% to 60% reduction in the factor XIIa activated cleavage of high molecular weight kininogen, and this effect lasted out through day 84 for the 300-milligram dose and to the latest available time point at day 56 for the 600-milligram dose. The magnitude of this effect is similar to that produced by lanadelumab in healthy subjects, but consistent with the long half-life that we have seen with STAR-0215 is well beyond that reported for lanadelumab. Importantly, this level of activity is consistent with the level of inhibition of plasma kallikrein shown to prevent HAE attacks with lanadelumab. Here, we are focused on the 300- and 600-milligram dose levels as there were no significant changes in the cleavage of high molecular weight kininogen over time following placebo and only small insignificant effects following the 100-milligram dose. Turning to the next slide. As we have shown you, early proof of concept of STAR-0215 as a potential long-acting preventative therapy for HAE has been achieved. The data support the designed favorable safety and tolerability profile for STAR-0215. Estimated half-life for STAR-0215 is up to 110 days with sustained concentrations consistent with clinical benefit for at least 3 months after a single dose and robust target engagement was seen with reduced cleaved high molecular weight kininogen for at least 3 months at levels that are associated with clinical benefit in HAE. The results that we have reviewed today provide a clear signal to proceed in the clinic to study STAR-0215 in patients and bring the potential of STAR-0215 one step closer to normalizing the lives of people with HAE. Now Chris will take us through the plans for our next clinical trial with STAR-0215 in HAE. Chris?

Thanks, Andy. Next up is the ALPHA-STAR proof-of-concept trial on Slide 20. This first-in-patient trial for STAR-0215 is expected to initiate in Q1 2023 and initial results are anticipated in mid-2024. This global trial will have single and multiple dose cohorts. Each qualified participant will receive at least one dose of STAR-0215 and after enrollment, participants will be eligible to join a long-term open-label trial that we anticipate starting in time to enroll the first completers of the ALPHA-STAR trial. We expect that the results from this proof-of-concept trial will determine whether STAR-0215 has durable activity, compatible with robust clinical benefits in people living with HAE for at least 3 months after dose administration. The results from this trial will be used to select doses for continued development, including the anticipated pivotal Phase III trial and additional details are now shown on the next slide. ALPHA-STAR is an open-label Phase Ib/II proof-of-concept trial in HAE. This trial will enroll patients with HAE types 1 and 2 and who have had at least 4 HAE attacks in the last year regardless of the therapy. In the run-in period that precedes STAR-0215 administration, participants need to have at least 2 attacks before qualifying to receive the study drug. Patients can't be receiving other preventative therapy during the trial. So if they were on preventative therapy, they'll have to stop that therapy before entering the run-in period. On-demand treatment will always be available to participants. Regarding endpoints, as the first-in-patient trial, the primary endpoint of safety. The secondary and exploratory endpoints include changes in HAE attack rate, PK, PD and quality of life assessments. Efficacy and safety comparisons will be made against data collected during the 8-week run-in period. Doses have been selected to provide dose-ranging information. As you see 2 dosing cohorts or planned. Cohort 1 is the sentinel cohort, in which we plan to assess the effect of a single dose of 450 milligrams of STAR-0215. This dose was selected because modeling shows that it has the potential to provide a profile associated with benefited patients for more than 3 months. In cohort 2, we plan to assess the effects of 600 milligrams and 300 milligrams doses with 3 months separating the 2. The dosage for this cohort may be adjusted after evaluating sentinel data from cohort 1. There is no placebo dose in the open-label trial. Based on the Phase Ia data that we've shared, it may be possible that the beneficial clinical effects the STAR-0215 makes and beyond 3 months of administration. To assess this, we're following subjects for up to 6 months after the last dose to assess durability of effect. This treatment period in cohort 2 will commence after an initial PK check in cohort 1, and this cohort will run in parallel to cohort 2. This cohort will enroll up to 14 people with HAE. We are planning to initiate a long-term open-label trial as well. Participants in the ALPHA-STAR trial will be eligible to roll into the long-term open-label trial once it is open for participants who continue to receive STAR-0215. Moving on to Slide 22. As we plan for trial enrollment, we've built a multifactor approach for operational success includes -- that includes focus on 3 domains: reducing protocol burden, optimizing site activations and engaging communities. To reduce protocol burden, we have removed the placebo group and built in frequent remote contacts for monitoring its support as well as personalized assistance for visits. To optimize site activations, we plan to have a global footprint with multiple sites focused on regions with efficient start-up processes. Country selection has been informed by the eligibility criteria of the trial. Regarding engaging communities, the trial has been designed with feedback from patients and trialists. We have been working in close partnership with advocacy groups within the clinical and patient communities on trial awareness and recruitment. And we are planning the long-term open-label trial, which may provide continued long-term access to STAR-0215 to participants, and this is an important initiative that will build trust with our communities. Turning to the next slide. I'll conclude with an overview of our clinical development plan for this program on the path to registration. We have just reviewed our plans for ALPHA-STAR, where preparation activities are ongoing and with trial initiation expected in Q1 with initial results from the single and multiple dose cohorts in mid-2024. We are also planning to add cohorts to the ongoing Phase Ia trial in healthy subjects to provide an opportunity to learn about the potential for a 6-month dosing with STAR-0215 and can expect initial results in Q4 of next year. We also expect final results from the first 3 cohorts of this trial in Q4 of next year. As I've also mentioned, we are planning the long-term open-label trial to assess long-term safety and clinical effects of STAR-0215 in HAE. We are at the early stages of planning a potential Phase III pivotal trial here after consultation with the relevant health authorities and assuming favorable data in the proof-of-concept trials. We anticipate a randomized blinded placebo-controlled global trial that will assess the efficacy and safety of STAR-0215 in HAE. Our Chief Commercial Officer, Andrew Komjathy, will now touch on the market opportunity. Andrew?

Thanks, Chris. Let's move to Slide 25. So as we've shared with you previously, the HAE treatment market is substantial and it's growing. Global HAE market was greater than $2 billion last year and is expected to nearly double by 2027 to $4.5 billion. This growth is driven by earlier patient diagnosis, more patients taking preventative treatments and finally, the expansion of available treatments in more geographic regions. Turning to Slide 26. The therapeutic landscape for preventative HAE treatment has evolved from highly burdensome products like CINRYZE and HAEGARDA are administered intravenously and subcutaneously twice a week; to include TAKHZYRO, the global market leader, which is administered subcutaneously once or twice a month; and ORLADEYO, a daily oral treatment. The 2 most recent entrants, TAKHZYRO and ORLADEYO together currently dominate the global HAE market and provide a validated mechanism of action for attack prevention. And while recent entrants and late-stage programs attempt to decrease the treatment burden, there remains a need for an effective treatment with infrequent dosing that can help normalize the lives of HAE. This is why we're so excited about the possibility of STAR-0215 to become a treatment that is not only highly effective in reducing attacks, but also reduces dosing frequency to 4 times a year or less. Our enthusiasm for STAR-0215 is supported by both HAE treatment providers and patients. I'll start with providers on the next slide. So we interviewed 20 U.S. physicians where we shared 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. We assess the potential of STAR-0215's target profile by asking physicians to rate on a 7-point scale, how likely they would be to prescribe such a product to their HAE patients. The average prescriber rating was at 6.5, indicating a high motivation to prescribe such a profile. This positive potential of STAR-0215 profile was also confirmed by a recently completed survey of HAE patients. If we turn to Slide 28, we surveyed 101 patients and shared the same blinded profile of STAR-0215 as discussed on the prior slide. We were very interested in understanding patient willingness to try a treatment with this profile. As shown on the graph on this slide, 69 of all patients surveyed were very willing to try it. 50% of patients taking only on-demand treatments were very willing to try STAR-0215, indicating a potential for STAR-0215 to grow the market for preventative treatment. Further, 68% of patients, who considered themselves very satisfied with their current treatment, were very willing to try STAR-0215, suggesting a high potential rate for treatment switching. These results support the potential for STAR-0215 becomes the new standard of care for attack prevention and help normalize the lives of patients with HAE. I will now hand the things over to Jill for some concluding remarks. Jill?

Thanks, Andrew. Moving to Slide 29. In summary, we are thrilled that STAR-0215 has shown early proof of concept for its target profile, a long-acting preventative therapy for HAE, a best-in-class PK profile and dosing once every 3 months or less frequently. As Chris reviewed, activities are underway, and we expect to initiate the outputs in our trial in HAE patients next quarter with initial results in mid-2024 from the single and multiple dose cohorts. Given the results we presented today, we believe there could be an opportunity to dose STAR-0215 less frequently, and we are planning to evaluate this with cohorts added to the current trial. We expect results in the fourth quarter next year. As we think about the future, we are excited about the potential of STAR-0215 to provide long-acting effective attack prevention for people living with HAE. Market research indicates that there is very high interest in a preventative therapy with a profile like we envision for STAR-0215. 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 both disease burden and treatment burden to enable the HAE community to spend substantially less time thinking about and managing their disease. With that, I'll ask the operator to open the call for your questions. Thank you.

[Operator Instructions] Our first question will come from the line of Eun Yang with Jefferies.

Great data. Congrats. A few questions. On the PD data, there is no error bar presented. So can you talk about the individual variability? And then I have a couple of questions on the dosing. So you are using fixed doses versus weight-based. So is there any particular reason why you use the fixed dose? And on the 6 months of dosing trial, you are planning in healthy volunteers, what doses are you thinking about exploring?

Great. Thanks, Eun. I'll hand the PD question over to Andy to describe the data that was presented for the 300- and 600-milligram dose cohorts in the PD assay.

Yes. So we're not showing error bars. The error states the variability was actually consistent with what Dyax actually shown in their normal healthy volunteer study. But importantly, the effects at the 300- and 600-milligram dose was statistically significant reductions in the cleavage of high molecular weight kininogen at the time points following dose administration. And as I said, with the 100-milligram dose, where there was a trend, they were not statistically significant. As we collect more data and we present the full data set, we'll obviously be putting error bars on those figures.

And to address your next question about the additional cohorts being added to the Phase Ia healthy subject trial, I'll let Chris answer that question.

Yes, thanks. You also asked about why we used a fixed dose versus weight-based dose. Our eyes are on getting us to patients as quickly as possible. And we think that a patient-friendly approach would be to use a fixed dose rather than a weight-based dose. So we've opted to move forward with fixed dosing. We anticipate that we'll be able to use the available data from the Phase I study and the incoming data from the patient study when they start to come in to help us understand the effects of various parameters such as cleaved on pharmacokinetics and use that information for final dose selection. Regarding the doses for the additional cohorts in Phase I, we are excited about the possibility of this being delivered potentially every 6 months. To get there based on the half-life that we have, we believe that we will need to have either a higher initial dose or to test whether a potential induction regimen would get us to maximum concentrations that would slowly decline, keeping concentrations well above that threshold for a 6-month time period. So we're getting close to being able to disclose the dose levels towards the study, but we haven't got there yet.

One moment for our next question that will come from the line of Hartaj Singh with Oppenheimer.

Great. A couple of questions. And again, really, really nice data and way to execute. Just a couple of questions. This is actually a little bit maybe more talking to the market opportunity. Can you just remind us again sort of what the breakdown is between sales in HAE, right, between the United States and ex U.S.? And the reason I ask is, when Alexion launched their long-acting ULTOMIRIS -- long-acting SOLIRIS called ULTOMIRIS, they actually saw a greater penetration and faster uptake in Europe and Japan. And the reason was because it lessened treatment burden and financial burden actually pairs and patients wanted to uptake it further. So maybe just walk us through a little bit about the ex U.S. opportunity and how that could also help from strategic considerations with partners? And then I just got a quick follow-up question.

Sure. This is Andrew. So the breakdown of sales for HAE kind of mirrors the broader rare disease markets. And based on the work we've done, about 70% of total sales come out of the U.S. and about 28% to 30% come outside of the U.S. From a patient number, those numbers are a little skewed ex U.S. And really the difference there is the higher pricing levels that can be achieved in the U.S. relative to the other markets. It's about a 70-30 split.

Great. And then my follow-up question is, again, just kind of looking forward, what kind of biomarkers could help you in the various data you're accumulating next year, that could also help with your Phase III design? And I guess what I'm trying to get at is that could you design a Phase III that would be smaller, more compact and faster to move along with biomarkers that will be validated by the FDA and so help you potentially get this really nice therapy to market faster?

Yes. Thanks, Hartaj. It's obviously something that we've been thinking deeply about. Our goals are the same as you articulated, getting to patients as quickly as we can. The biomarker is currently used to help us determine the activity of the inhibitor against plasma kallikrein, this is cleaved high molecular weight kininogen. And it does appear to correlate with benefit. However, it loses some sensitivity as we get to the decrease in cleaved high molecular weight kininogen that's in the range that we currently have achieved, there doesn't appear to be a dose-related response beyond that, meaning that increasing the dose doesn't get you more cleaved high molecular weight kininogen, although we suspect that there would be some changes in efficacy. So unfortunately, I think that particular biomarker isn't going to help us. However, we think that we can be using pharmacokinetics as well as patient response in terms of attack frequency to develop a pretty tight trial for Phase III. We can also take advantage of a synthetic control arm or other maneuvers to help decrease the overall placebo burden of our Phase III trial that will allow for more facile execution.

One moment for our next question that will come from the line of Sam Slutsky with LifeSci Capital.

Congrats on the update. A few for me. So as you pointing out injection site reactions of about half the rate lanadelumab, can you just walk through the background again as your formulation versus lanadelumab and then why lower injection site reactions make sense? And then I guess on top of that, were any headaches noted in your study? And then any reason why we see headaches with lanadelumab?

Chris, do you want to take that?

Yes, I sure, will. So we had 25 people received single dose of STAR-0215 and we had 6 related treatment emergent adverse -- about 6 subjects with treatment emergent adverse events. They were more commonly seen in the higher dose levels. At this point, the data are sub-blinded. So frankly, we don't know whether any of these were seen in placebo subjects. And as you know, you saw from the slides, the most comment ISR associated with our profile is site redness, which occurs shortly after the administration. Commonly with lanadelumab administration, pain is experienced. And the one reason for that, we believe, is that formulation for lanadelumab is citric based and that citric acid can cause a painful stinging sensation during administration. We've been aware of this for a while. And when we formulated STAR-0215, we were very purposeful and engineered out the citric acid. So we think that, that converts a potential advantage. Obviously, as we dose more subjects, both healthy and get implication, we'll assess that more completely. And then regarding headaches, the headache data are interesting. We had 1 subject with a headache in the Phase I trial, it was mild and resolved. Headaches are pretty common. So it's tough actually to find relating this with headaches even though PIs and even sponsors try to do so. Lanadelumab headache rate was a little higher than we expect, and we don't understand mechanistically why that could occur. There were headaches also in the placebo group. So it could be that there was really no substantial difference between the 2 events.

Got it. That's helpful. And then just last question. So based on real-world data from Takeda, it looks like about 70% of patients on lanadelumab are on the every 2-week dosing schedule, whereas you could be every 3 or 6 months based on the data today. I guess could you just remind us of other markets for a notable increase in dosing frequency has led to strong market share?

Yes. Andrew?

Yes. Sure. There are a few that we've looked into. Multiple sclerosis is a good example where the market started with frequently dosed injectables kind of move to oral and now the market entrant is at 6-month IV. We've also seen similar dynamics in psoriasis and hemophilia. So those are at least 3 markets where a later entrant that provided efficacy, but also reduce the burden of treatment, we're able to take market leadership. .

One moment for our next question that will come from the line of Laura Chico with Wedbush.

I just have 2 questions. One, on the reported half-life, I know the press release is saying up to 110 days. And I believe you're still waiting for additional data from the 600 mg cohort. But is there any way you can clarify what the estimated half-life is for the 300 mg dose cohort at this point?

Yes. This is Chris. Happy to do so. The estimated half-life for the 300-milligram cohort is 110 days. The estimated piece comes from the fact that we're not done monitoring these subjects. And even at the age where there's a substantial amount of drug on board still for every subject. So we just need more data before we can take out the word estimated in front of the word half-life. And the up-to piece is because these are still preliminary data, and we're trying to be relatively conservative in what we say here in describing what we think the projection for the half-life is.

That's super helpful. Okay. And then I wanted to tease into the every 6-month dosing a little bit further. I know you had some great market research data there. Trying to frame this a little bit more. Is this more of a nice-to-have or a must-have? And I guess the reason I'm asking some of the KOL feedback has -- that we've gotten has articulated more of a preference for something that's more aligned with a 3-month option versus 6. But obviously, it's a pretty competitive environment. So just wondering if you can kind of walk through the strategy there and frame that out a little further.

Yes. Maybe I'll start and hand it to Andrew. These data are fresh for us. And when we saw PK and PD, it's certainly pointed to the potential of being able to dose less frequently than 3 months. And hence, the concept for testing in every 6-month regimen. With that said, we need to do some more work to understand what patients want and what physicians want. I think Andrew can speak a little bit to that from the preliminary research we have done previously and also how we see the market evolving.

Yes. So the market research that I touched on earlier, we really looked at the profile of subcutaneous dose every 3 months. So we did not explore 6 months. Next steps are obviously to kind of look at a dosing option like that. And as you can see, the results were fairly compelling. I would go back to maybe some of the markets I may have highlighted earlier, where as the market evolves to less frequent dosing, there was an increase in share for that particular product. I would also say that a 6-month dose could line up very nicely with how often the physicians and the patients see each other. So we still intend to make sure that this is a patient-friendly dose that can be self-administered, but it may time up very nicely for those visits to coincide with that dosing regimen. So more to follow. I do think that there are people that are really looking for ways to normalize their life with less treatment. And I think if we can provide a dose of 6 months, I think there'd be a high appetite for something like that.

One moment for our next question and that will come from the line of Joe Pantginis with H.C. Wainwright.

Very nice profile building data. So 2 questions, please. So first, I just wanted to go back and try to get a little more focus on the strategic NBD arena. So I guess, generally, first, what is your current view on business development for the asset? And when you boil down a little further, business development, I think, is much more needed, say, for example, in Europe where you have to get approved on a country-by-country basis, so maybe needing someone that has more wherewithal unless you build it yourself to do that blocking and tackling? And then how do you feel Phase I healthy volunteer data, which are quite striking, can impact any thoughts towards BD, whereas maybe for other indications, healthy volunteer data wouldn't move the needle at all?

Yes. Thanks for the question. Nice to talk with you. So as you well know, there is definitely a lot of interest in the HAE space. At this time, we haven't formalized our plans for our global strategy with STAR-0215, but we'll be certainly thinking deeply about that over the coming months as we think about the best way to bring this drug candidates to patients. And so more certainly to come from there. And you had a second question.

The Phase I data, how do...

Yes. Thanks. Yes. And I think you're absolutely right. This feels like different Phase Ia data. This is a clinically validated mechanism for HAE. So we see these data as quite meaningful in establishing STAR-0215 and its potential in this disease area. We've hit PK objective we were looking for and the PD objective we were looking for. So I think at least certainly in our eyes, these are meaningful data that are quite encouraging for the program.

No, that's helpful. And then just quickly, I guess, on ALPHA-STAR, since you did mention, obviously, and it makes sense, that on-demand therapy will be always available for patients. What level of -- or how did it ever play into your decision to include a placebo arm in the study? And if not, why?

Chris?

Sure. So we had thought deeply about whether we would have a placebo group in the trial and heard resounding feedback from the clinical and in fact large parts of the clinical trial community, pilots, clinician, scientists to do trials that having a placebo group is number one, a distraction and a hindrance for patients that would be probably unwilling to participate, and two, not necessary. And so what we've done instead is we -- in lieu of the placebo group, we've built in a robust run-in period in which we have patients being followed very closely as if they were in the placebo trial for a strong record of their baseline attack frequency and 8 weeks, we believe, is long enough to get that strong record. It will also provide us a sense of baseline safety information as well as baseline PK and PD information. So we have that built into the trial to allow us a robust data set to compare clinical effects, I guess.

One moment for our next question and that will come from the line of Michael Higgins with Ladenburg Thalmann.

Congrats guys from me as well on the terrific data. Question for you, if I could, on the Phase Ia and healthy volunteers for a potential 6-month dosing. Is the design allowed such that you can use this data and possibly consider a 4-month dosing regimen? And the back half of that question being, can you adjust alpha, can you adjust future clinical trials, if you should find that maybe 4-month dosing is preferred or if you find that you can -- you find you could do a 4 months, you'd just rather say 3 months for, I guess, convenience sake, maybe it's a bit easier.

I'll hand it to Chris.

Yes. So the short answer is yes. We do anticipate that even a dose level like the 450-milligram dose models out to be potentially effective for 4 months -- every 4 months kind of dose frequency. With the incoming data from planned additional cohorts, we should have enough pharmacokinetic data and pharmacodynamic data to give us a good sense about the potential effects in patients at various dose frequencies and dose regimens. There is some appeal to a [ q.] 4-month regimen 3 times a year is really strong, and we will certainly be working with Andrew and his team to help us retain how would that impact the normalization goal that we have in mind for STAR-0215.

Makes sense. And then just one other, if I could here. You mentioned dose-related injection site reactions. Are the patients prepared in any way, shape or form, is the skin prepared anyway prior to the injection?

Just with cleansing alcohol wipe.

And we do have a follow-up from Eun Yang with Jefferies.

A couple of questions on dosing and one other question. So in HAE patients in cohort 1, you are testing 450 milligrams. I'm kind of wondering why you chose that dose. Although the injection site reactions were all grade 1, were there more frequent AEs at 600 milligrams? So that's question number one. Number two is that in cohort 2, I just want to clarify the 600-milligram is a loading dose, then patients are getting 300 milligram? Or are there 2 dosing cohorts? And the last question is on the clinical benefits. So lanadelumab showed about 80% or higher the attack number reduction, but more importantly, percentage of patients experiencing attack free is around 40%. So when you're looking into your dose range, are you trying to improve the percentage of attack-free patients? Or is it more of like maintaining the efficacy similar to lanadelumab and trying to find a better dosing regimen?

Yes. Chris, it sounds like there are 2 questions there for you.

Yes. Great, thanks again. So thank you for asking about the ALPHA-STAR trial. We're excited to get this kicked off for patients and trialists, and we're looking forward to getting to starting next quarter. So cohort 1 is 4 subjects with 450 milligrams given once. And we chose this because we think it has the potential for clinical benefit out -- beyond 3 months. And this could provide very early read on proof of concept in patients defined as, jumping at to your question 3, a strong reduction in attack frequency and a high proportion of patients who are attack-free. The injection site reactions, I did say that what we saw in the Phase I study shows that there were more in the 300 and 600-milligram cohorts than in the 100-milligram cohort. The 450 milligrams based on the current formulation would be 2 injections. Current formulation is 150 milligrams per ml. So that would be one 2 ml injection followed by one 1 ml injection. But we are doing additional work to potentially improve upon the concentration in the formulation, which would reduce the injection burden. And ultimately, the goal here is to get the POC data on efficacy so that we can pick doses for the Phase III trial. Your next question was about the clarification question on cohort 2. That is one cohort. So the subjects enrolled in that up to 14, who received one dose of 600, 3 months later will receive one dose of 300 milligrams. And then your last question was about the efficacy bar or our expectations around that. So we love this question, because we think that with this profile, the PK profile in particular, we're going to have long time periods where we have drug concentrations about the threshold needed for clinical benefits. But this means is that there are no dips in concentrations that increase the risk for an attack in a 3-month period. Whereas with monthly injections, there would be 3 dips, but we just have one that gets close to the very end. At those dips when the concentration is low, and so the protection against searching plasma kallikrein is low, and that's when attacks have a strong likelihood to occur. So we feel like there is potential to improve upon the overall rate in reduction in attacks and to improve upon the proportion of people who are attack-free, and we aim to be able to get our first read of that in the ALPHA-STAR study.

I'm showing no further questions in the queue at this time. I would now like to turn the call back over to management for any closing remarks.

We are thrilled that STAR-0215 has shown early proof of concept as a potential long-acting preventative therapy for HAE with its best-in-class PK profile that supports dosing once every 3 months or less frequently. The Phase Ia trial has achieved the desired objectives for safety and tolerability, half-life and pharmacodynamic activity. Thank you very much for joining us today. Today, we are one step closer to our goal of reducing the disease burden and treatment burden for the HAE community. We look forward to keeping you all updated as we achieve additional milestones with STAR-0215. Andrea?

That concludes today's call. A webcast replay will be available for 90 days via the Investor Relations page on our website at www.astriatx.com. Thank you.

Thank you for participating. This concludes today's conference call. You may now disconnect.