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

Good morning, and welcome to the Astria Therapeutics Officer Initial Results Conference Call. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be available on the Astria website following the conclusion of the event. I'd now like to turn the call over to Liz Higgins, Director of Communications and Investor Relations at Astria Therapeutics. Please go ahead, Liz.

Thank you, Tara. Welcome to today's Astria Therapeutics ALPHA-STAR Initial Results Conference Call. With me today are Jill Milne, Chief Executive Officer; Christopher Morabito, Chief Medical Officer. And also available for questions, we have Noah Clauser, Chief Financial Officer; Andrew Komjathy, Chief Commercial Officer; and Andrea Matthews, Chief Business Officer. We issued a press release this morning announcing that we have shared positive initial proof-of-concept results from the Phase Ib/II ALPHA-STAR trial in HAE patients. The press release is available on our website. We are also using slides during today's call that are available within the Events and Presentations section in the Investors part of our website. I would like to note that during today's presentation, as mentioned on Slide 2, we will be making forward-looking statements related to our business based on current and future expectations. Actual results may differ materially 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 judgment as of today, and we undertake no obligation to publicly update any forward-looking statements, except as required by law. Jill?

Thank you, everyone, for joining our call this morning. We're thrilled to have the opportunity to share initial results from our ALPHA-STAR Phase Ib/II clinical trial of STAR-0215 in HAE patients. These results are particularly meaningful for the HAE patient community who are at the center of everything we do here at Astria. We know from their experiences how burdensome HAE treatment options are, and we now have initial data that support our vision for STAR-0215 as a safe, highly effective and pain-free first choice treatment with dosing every 3 and 6 months, enabling people with HAE to live life without limitations. An HAE patient, Kim Wilson, came to our offices recently to share her story. And she said, not having to think about taking a medication except for 2 or 4 times per year would be incredible. The opportunity to be able to forget about my HAE is something I never thought could happen. With her words top of mind, we are looking forward to sharing these data with you today and demonstrating how we believe we can help enable Kim and many others to forget about HAE. I will kick things off today with an overview of our vision and strategy for Astria and key takeaways from our exciting results. Chris will then walk through the results in more detail and review our plans for the Phase III program. Next, I will look to the future for how I believe Astria can become leading allergy and immunology company. We'll then open it up for Q&A. Our focus for Astria is to develop first choice products that improve the health outcomes of patients with allergic and immunological diseases. First choice to us means patients and treating physicians choose our products because of their strong competitive efficacy, low treatment burden, and favorable safety and tolerability profile. Our pipeline is focused on established mechanisms, mechanisms that are clinically validated where we believe we can advance ultimately best-in-class programs. Very much in line with this strategy is our STAR-0215 program. We think that STAR-0215 is very well positioned to be the first choice preventative treatment to help normalize the lives of patients living with HAE, a rare, life-changing and, at times, life-threatening disease. HAE is characterized by severe uncontrollable and debilitating swelling that can affect the face, limbs, abdomen and airways. Swells are painful and unpredictable. And we are excited for the opportunity for STAR-0215 to potentially become the first choice therapy in this disease. Also in our pipeline and aligned with our strategy is STAR-0310, our second program, which is an anti-OX40 antibody that we are developing as a potential best-in-class therapeutic for atopic dermatitis and potentially other indications. To advance our vision of making a difference in the lives of people living with allergic and immunological diseases, we have assembled a team of experienced individuals with broad set of capabilities spanning discovery through commercialization. Our strong cash position supports our plans into mid-2027, which include a Phase III pivotal trial for STAR-0215. Let's turn to Slide 5 to review what we believe sets STAR-0215 apart and why we believe it has the potential to be the preventative treatment that patients and physicians turn to first in HAE. STAR-0215 is a monoclonal antibody inhibitor of plasma kallikrein, which is the same mechanism of action and the same modality as the market leader TAKHZYRO. We believe this gives us an advantage with a clear regulatory path forward and with patients who understand and trust the way that STAR-0215 works to prevent their HAE attacks. Based on the data we have seen to date, STAR-0215 also has the potential to reduce both treatment and disease burden, supporting rapid, robust and durable efficacy and the potential for dosing only 2 or 4 times per year. This potential dosing profile is enabled by the YTE technology in the Fc domain of the antibody, which extends the half-life. We also have developed STAR-0215 to be self-administrable and formulated to reduce injection site pain to be as patient friendly as possible. The ALPHA-STAR Phase Ib/II trial of STAR-0215 was designed with 2 purposes in mind. First, to assess the safety and efficacy profile of STAR-0215 in patients. And second, to enable plans for Phase III. We built an interim analysis into this trial to give us an early look at data, and if warranted, to advance our plans for Phase III. Due to faster than originally planned enrollment, a result of interest in the trial, and the excellent work of our internal team, we are able to report the initial data today, earlier than we originally expected. We are pleased to report that the initial results, which Chris will go through in a moment, have exceeded our expectations and allow us to advance our plans for Phase III. We believe that STAR-0215 has the potential to change the way people live with their HAE. We would like you to take away 3 key points from today's presentation. First, these positive initial proof-of-concept results support the potential to dose STAR-0215 once every 3 and 6 months. Second, we plan to initiate a pivotal Phase III trial in Q1 of 2025 and expect to report top line data by year-end 2026. Third, the positive data we are sharing today also support our belief that STAR-0215 can become the market-leading treatment for HAE. I will now turn the presentation over to Chris, our Chief Medical Officer, who will review the ALPHA-STAR results with you in more detail. Chris?

Thanks, Jill. We are excited to be able to share with you the initial results from the Phase Ib/II ALPHA-STAR trial. ALPHA-STAR is a single and multiple dose, dose ranging, proof-of-concept, open-label trial of STAR-0215 in adults with HAE Type 1 or 2. There are 3 cohorts in this trial. Cohort 1 is a single dose of 450 milligrams, which was predicted to maintain target concentrations for at least 3 months. Cohorts 2 and 3 include dose regimens for a potential Q3-month dose 600 milligrams, then 300 milligrams Q3 months, and a Q6-month dose, 600 milligrams, then 600 milligrams Q6 months, respectively. Each cohort is preceded by a run-in period in which baseline HAE type rates are determined. Each follow-up period is 6 months after the last dose received. This long follow-up after the last dose is a critical design element of this trial. During the tail end of the follow-up, the last 3 months, where STAR-0215 concentrations were predicted to wane, we anticipated attacks might occur. Those data are an important element of the dose-ranging nature of this trial. The trial enrolled these 3 cohorts sequentially. Target enrollment of 16 patients has been achieved and all doses have been administered. In this trial, we are evaluating safety, efficacy, PK and PD and 3 cohorts for up to 6 months after the last dose administered. Today's initial data are safety and efficacy data cumulative to March 13, 2024. We aim to establish proof of concept of STAR-0215 as a long-acting preventative treatment for HAE given as infrequently as once every 6 months. These initial data confirm proof of concept, as I'll review with you in the next slides. Further, these results provide data to support our planned upcoming discussions with global health authorities in order to finalize plans for Phase III. ALPHA-STAR has enrolled a total of 16 patients, all with Type 1 or Type 2 HAE. Target enrollment was achieved at HAE centers in the U.S. and Canada. There has been strong interest in this trial, and it has enrolled faster than our expectations. The eligibility criteria require that patients enter the run-in period washed off from preventive therapy use. Two patients stopped taking lanadelumab for the required 3-month washout period before rolling into our trial. The baseline HAE attack rate was approximately 2 to 3 attacks per month, in line with our expectations based on the trials eligibility criteria and consistent with HAE clinical trial of preventatives. And these initial results, STAR-0215 achieved rapid and durable reductions in HAE attacks. I'm showing you a swimmers' lane plot, which displays each occurrence of HAE attack for each participant for the full length of follow-up. The color relates to the attack severity and the thickness relates to the duration of the attack. The boxes show the total duration for each cohort, including 6-month follow-up period after the last dose. The shaded bars show the duration of follow-up in this [indiscernible] cut. As shown in Cohort 1, all 4 participants have completed 6 months of follow-up. In Cohort 2, all 6 participants have completed 3 months of follow-up and 3 have completed 6 months of follow-up. And in Cohort 3, 4 participants have completed 3 months of follow-up. As you can see, the incidence of attacks during the run-in period, and can compare that to the incidents in the treatment period. The impact is rapid. And the impact is durable. You can see robust reduction in attacks through 6 months after a single dose in Cohort 1 and after 2 doses given at or before 3 months in Cohorts 2 and 3. On the next slide, these are data describing the monthly attack rate reduction. This measurement is typically the primary endpoint in Phase III trials of -- in HAE. Based on the design of the trial, we anticipated that we'd see about 80% to 90% reduction in monthly attacks compared to baseline. These results exceed our expectations. These data show 90% to 96% reduction in HAE attacks compared to baseline out of the 6 months -- out to 6 months from initiation of treatment after 1 or 2 doses of 215. When we look specifically at follow-up through 3 months, the attack rate reduction is 90% to 96%. And when we look at the first full 6 months of follow-up after the initiation of treatment, the attack rate reduction is 92% to 96%. In addition, when we analyzed the cumulative all available follow-up attack rate reduction, including participants with over 6 months of follow-up, there's a 91% to 94% attack rate reduction. These data demonstrate that the impact of 215 on HAE attacks is durable, supporting the ability to administer 215 once every 3 months and once every 6 months. As you noticed from the swimmers' lane plot, there was a substantial proportion of participants who were attack-free. For the first 2 months of treatment, counting immediately from day 1, 50% to 67% of participants were free from attacks. In Cohort 2, in which participants received a lengthy Phase III dose regimen, 67% were attack-free through 6 months. In Cohort 1, freedom from attacks was durable past 3 months, despite intentionally designing this cohort to have waning drug concentrations after 3 months. This is an early read of what we may expect to see regarding this important endpoint in a larger Phase III trial that would be designed to assess attack-free rates, and I'll talk about that more in a few minutes. In the next 2 slides, I'll show you data which show that STAR-0215 has the potential to reduce the burden of the disease. These are data showing the reduction in severity of HAE attacks. Shown here are moderate and severe attacks only. 215 reduced the number of moderate and severe attacks compared to baseline by 92% to 100% at 3 and at 6 months. And after treatment with 215, there were no severe HAE attacks. On the next slide, you'll see data showing the change in the rate of attacks requiring rescue medication use. Shown in this graph are attacks requiring the use of rescue medication. Similar to the previous slide regarding attack severity, these data show a large 91% to 95% decrease in the number of attacks for which rescue medications were used. These data suggest that the use of 215 in patients with HAE may be associated with a very low need for on-demand treatment for an acute attack. Moving on now to pharmacokinetic and pharmacodynamic assessments. We see that the PK and PD changes are supportive of the clinical efficacy I just reviewed with you. Here are the interim PK and PD data that we have so far. Regarding PK, the concentrations over time profiles are similar to what we expected based on the Phase Ia healthy volunteer data. There is a rapid increase in STAR-0215 concentrations after subcutaneous administration in all 3 cohorts. Concentrations remain above the initial target PK level of 12 micrograms per ml for more than 3 months in all cohorts, and well above 12 micrograms per ml in Cohorts 2 and 3 for the duration of available follow-up. In Cohorts 2 and 3, where we have been testing the feasibility of a potential Q3-month dose regimen and a potential Q6-month dose regimen, respectively, concentrations are continuously above the previously identified concentration threshold. As expected, in Cohort 1, which was a single dose of 450 milligrams, concentrations decreased over time, falling to less than 12 micrograms per ml after about 4 months. This anticipated decrease predicted from the healthy volunteer data we've presented previously was a critical part of the design of the trial. Despite this decrease, the efficacy in this cohort remained strong through at least 6 months after that one single dose. While it's still early, the continued clinical benefit, despite waning concentrations, could mean that the 12-microgram per ml bar is, in fact, conservative for 215 and/or 215 is more potent than lanadelumab. To assess pharmacodynamics, we evaluated change from baseline and cleaved high molecular weight kininogen. As cleaved high molecular weight kininogen is produced directly by plasmic kallikrein, it is a strong biomarker for PD effects from a plasma kallikrein inhibitor like STAR-0215. These data show that we are meeting the expected level of change of about 53.7% change from baseline informed by lanadelumab's Phase III data as the maximum steady state reduction. Together with the initial efficacy and safety data, these PK data demonstrate that Q3 month and Q6 month dosing has a potential to achieve robust clinical benefits for patients. I'll share with you now the data regarding safety and tolerability, which is the primary endpoint of this trial. As I said earlier, target enrollment has been achieved and all participants have received their prescribed doses. The data suggests that 215 has a favorable safety profile and appears to be well tolerated. There were only 2 related treatment emergent adverse events, one of which was an injection site reaction that occurred 5 days after the second dose in Cohort 3. This was mild and lasted less than a day. The other was mild dizziness. There were no SAEs, no discontinuations and no clinically relevant changes in clinical laboratory values or ECG parameters. Importantly, since other HAE medications can be associated with pain with injections, there have been no reports of injection site reactions of pain with 215. In summary, these initial data provide proof of concept of 215 as a long-acting preventative therapy for people with HAE, and that it may be administered as infrequently as once every 6 months. On this slide, we want to contextualize our data compared to the current market leader, lanadelumab. Shown here at the top of the slide are summary results from all cohorts and specifically from Cohort 2 through 6 months, which has been our first chance to test the potential effectiveness of what could be a Phase III dose regimen. To date, we have seen 90% to 96% reduction in monthly attack rates, 50% to 67% attack freedom rate for the first 3 months, 92% to 100% reduction of moderate and severe attacks, and 93% to 95% reduction in the number of attacks requiring rescue medications at 3 and 6 months. We have seen no evidence of injection site pain. And as noted, we would expect 215 to be administered 2 to 4 times per year. On the bottom half of the slide, we are showing lanadelumab Phase III data for the 300-milligram Q2-week and Q4-week regimens that are widely used. While the comparison represents a cross-trial comparison and does not involve data from a head-to-head clinical trial, STAR-0215, based on these initial results, appears to have comparable efficacy to lanadelumab administered at 300 milligrams every 2 weeks in most patients, which is 26 times per year. And it also appears to not have the risk of pain with injection associated with lanadelumab. It's early, and we have a small sample size, so we don't want to over-interpret this comparison. But the data we are showing today put wind in our sails and we believe point to a high potential probability of success for STAR-0215. Participants in ALPHA-STAR are eligible to enroll in the Phase II long-term open label trial, which we called ALPHA-SOLAR. In this trial, participants receive either 300 milligrams every 3 months or 600 milligrams every 6 months. Data collected from this trial will assess long-term safety, tolerability and clinical activity of STAR-0215, which we anticipate will support potential regulatory approvals. In order to accelerate the collection of data to support those -- these potential approvals, we're expanding the enrollment into ALPHA-STAR now and ideally ALPHA-SOLAR later up to a maximum of 6 more in Cohort 2 and in Cohort 3. With these compelling data, we plan to proceed to Phase III clinical development. In the next couple of slides, I'll provide an overview of our strategy and plans. Our strategy is to get STAR-0215 to patients as quickly as we can, partly for competitive and value-generating reasons, but more so because patients deserve better options than what they have now. But with such long-lasting benefit, we have a choice to make. Q3-month administration appears that it may work exceptionally well based on today's data, but we believe Q6 months and maybe longer may work too. But the Q6 month program would require longer trials to meet regulatory expectations. To achieve our goals, we intend to develop STAR-0215 for Q3-month and Q6-month administration in separate trials. Our approach is to focus on Q3 months first to get to market as soon as possible with a single pivotal efficacy trial. And then, as soon as enrollment for that trial is done, commence a Q6-month trial to enable a fast following label expansion. This approach puts us in the best competitive position possible. Moving now to an overview of our plans for the Q3-month Phase III trial, which we are planning as a single registrational trial. We anticipate that this will be a randomized, placebo-controlled trial assessing monthly attack rate reductions over 6 months. Over the next few months, we plan to discuss these plans with regulatory authorities to obtain feedback prior to finalizing the design. We plan to enroll approximately 100 adolescents and adults with HAE Type 1 or 2 globally. The size of the trial is dependent on establishing a robust safety data set as well as to assess advocacy. We expect the primary endpoint will be monthly attack rate reduction, the same measure that we presented today and the standard for pivotal HAE trials. The key secondary endpoint is planned to be the proportion of participants who are attack-free. By key, I mean that the trial will be specifically designed to provide robust data for this endpoint, which we believe is a potential differentiator for STAR-0215. For dose selection, the current data supports 600 milligrams as a loading dose than 300 milligrams Q3 months. And we expect to include that in this trial. The current data from Cohort 2, which has a similar design to this dosing regimen, shows strong efficacy on attack rate reduction and reductions in the burden of disease as well as favorable safety. We expect to initiate this trial in Q1 2025 with top line results expected by year-end 2026. Based on the data we've reviewed today, we also have strong conviction in the Q6-month program. The durable efficacy after 6 months and beyond, with supportive PK and PD results, suggest that we may be able to achieve similar efficacy to what we've shown here today when 215 is administered once every 6 months. And like the Q3-month Phase III trial, we expect that this will be a randomized placebo-controlled trial. Our current understanding is that this will be a 12-month treatment period, so about twice as long as the [ Q1 ] Phase III. We look forward to sharing additional details regarding plans with you. Jill will now review our plans for the future for both 215 and for Astria. Jill?

Thank you, Chris. We're excited about advancing STAR-0215 into Phase III. Based on these initial ALPHA-STAR results, we believe that STAR-0215 has the potential to lead the market for HAE treatments. To get a better understanding of how STAR-0215 could ultimately fit into the treatment landscape, we have conducted several market research studies with patients, physicians and payers. We asked them about a potential drug with efficacy similar to lanadelumab but dosing 2 to 4 times per year. We've discussed much of this research before, but I wanted to discuss it again today now that we have HAE patient data that supports this profile for STAR-0215, if not better. Let me share some of these results. Starting with patients in the left box on this slide. In a blinded quantitative market research survey of 101 HAE patients, we learned that 2/3 of them were highly interested in trying a product with STAR-0215's Q3-month target profile. And that included patients that were currently treated with on-demand only therapy, daily oral preventatives and injectable preventive medicines, including once monthly. These results show us that STAR-0215's target profile is highly interesting to patients regardless of their current therapy. We also conducted market research with HAE physicians and learned that 93% to 97% would be willing to prescribe a product with STAR-0215's target profile and anticipate prescribing a product with STAR-0215's target profile to nearly half of their future patients. On the right side of this slide, you can see our research with payers, where 100% of those interviewed felt that a therapy with STAR-0215's target profile should be covered, and they also said they would expect pressure from patients and physicians to have access to a therapy that would reduce dosing frequency significantly. The high level of interest from these 3 groups is exciting for the future of STAR-0215. Based on the initial results we have announced this morning, our market research and the HAE treatment landscape, we believe that STAR-0215 has the potential to lead the market for HAE treatments. We believe STAR-0215 could benefit all patients with Type 1 and Type 2 HAE, including mild, moderate and severe patients. We think that we can gain market share from patients who are taking injectables, orals and those only taking on demand. The efficacy, tolerability and very low treatment burden that we aim to offer with STAR-0215 can appeal to every category of HAE patients. We believe that patients on injectables would be interested in switching to STAR-0215 because of its potential for both reduced frequency of administration and low risk of injection pain. For patients currently taking orals, we believe that STAR-0215 will have better efficacy, less frequent administration and low risk of injection pain, making the transition from orals to injectables easier. For the patients that take on-demand only therapies, given STAR-0215's expected dosing frequency, it could actually reduce patients' total injection burden per year. We think that STAR-0215 can ultimately lead the HAE treatment market, which we expect to be $4.5 billion by 2027. Let's turn to upcoming milestones and important near-term events. For STAR-0215, our initial results today, we expect to share additional Phase Ib/II data later this year, and then we plan to initiate a Phase III trial for Q3M dosing in the first quarter of 2025, with top line results expected by year-end 2026. In mid-2025, we plan to share initial results from the ALPHA-SOLAR long-term open label study. These results will include data from patients receiving STAR-0215 dosed every 3 months and from patients dosed every 6 months. We are also looking forward to keeping you up to date on the progress of our OX40 antagonist program, STAR-0310 for atopic dermatitis. We plan to share information on its preclinical profile this year before an expected IND submission by year-end. We have a strong financial foundation to enable our vision for programs over the next several years. We expect our cash runway to fund the company into mid-2027, supporting the key activities for the development of STAR-0215 and STAR-0310, including the Q3-month Phase III trial top line results expected by year-end 2026, as well as associated activities delay the foundation for a strong future potential launch of STAR-0215, along with the IND submission and initial clinical results for STAR-0310. To summarize, our goal is to change the way people live with their HAE, and we are well on our way to achieving that goal. We are grateful for our close collaboration with the advocacy community and expert physicians, which enables patient-driven drug development to be at the core of our programs. We have the data now to quickly advance to Phase III with a fast-to-market strategy. The supporting activities are all on track, including the ongoing open label out of the SOLAR trial, Phase III preparations and a patient-focused device strategy. We plan to launch with both an auto-injector and prefilled syringe to continue to provide patients options to choose what works best for their lives. We have novel composition of matter IP for STAR-0215 expected through 2042 and potentially later. All of this together leads us to believe that there is incredible potential for STAR-0215 to become the market-leading first choice HAE treatment. I'd like to end by bringing the conversation back to our purpose and the reason behind the development of STAR-0215, our HAE patient community. We understand that people living with HAE are looking for more from their treatments, and we believe that STAR-0215 can be a therapy that they can trust will manage their disease while substantially reducing their treatment burden. Here we have Kim, who I mentioned earlier. Kim is living with Type 2 HAE. And despite experiencing her first attack as a child, she did not receive her formal diagnosis until 25 years later. Her story and her excitement for STAR-0215 is what drives us forward. We are excited for a future where people living with HAE have the opportunity to forget about their HAE due to a drug like STAR-0215. Thank you all for your time this morning, and we will turn it back to the operator for questions.

Great. Thank you, Jill. So at this time, we'll be conducting a question-and-answer session with our speakers. [Operator Instructions] So our first question comes from Laura Chico at Wedbush.

I guess I had 2. First one, with respect to the decision to do the 3-month and the 6-month interval, do you have a sense as to what dose you will be selecting for the 6-month regimen? I believe you called out one that you would be advancing for the 3-month regimen. And then one related to PK safety. Have you evaluated antidrug antibodies at this point?

Great. Thanks, Laura, for the questions. I'll start and then I'll hand it over to Chris to provide some more details. So for the -- you're right that for the Q3-month dosing regimen for Phase III, we think the data from Cohort 2 strongly supports that, that is a dose that has potential to be dosing our Q3-month trial. Let me hand it to Chris now to talk a little bit in more detail about that in the Q6-month.

Yes. Thanks, Jill. Thanks, Laura, for the question. Look, we're super excited about these data today. When we saw first the data from Cohort 1, 450 milligrams at 6 months, 92% attack rate reduction, it was far beyond our expectations. As you know, Cohort 3 is specifically designed to begin to assess what could be a Phase III dose regimen for Q6 months, which is 600 milligrams load, and 600 milligrams Q6 months. The initial data from that cohort looked good, too. We haven't seen the follow-up data. So today, I can't tell you for sure what the dose will be for that, but anything above 450 milligrams looks like it could work, and we'll get more data from 600 milligrams in Cohort 3 soon and be able to, not only share that with you, but also use those data for the decision around dose selection. And then for the antidrug antibody, we have not completed our assessment yet as these are just initial data. I will say that we have looked very carefully at every person's PK and PD curve. Nothing unusual is showing up. So if there are ADAs present, they're not impacting PK or PD at this time.

Our next question comes from Joe Pantginis at H.C. Wainwright.

Everybody, can you hear me?

Yes.

Great. Great. And congratulations on the data. I mean, obviously, with so many of us looking at this space for a long time, this is just one person's opinion, but these data are fantastic. So couple of questions. First, this one is a little in the weeds here. Do you have any information right now about the site of attack distribution and where you might have less efficacy, for example, versus how widespread the efficacy is depending on the site?

Great. Thanks for the kind words, Joe. As you gathered, we're very excited about these results as well. And let me direct that question to Chris.

Yes. So Joe, thanks for the question. At this time, we don't -- I will tell you that we saw mostly abdominal and peripheral attacks. I can't tell you today what the reduction from baseline was or the distribution of that. As you saw from our swimmer lane plot, which we're showing just about all the data that we have, there is a substantial decrease in the number of attacks, and those that are present are predominantly mild or moderate. So regardless of where they occur, we're still seeing a big impact on the burden of the disease for patients.

Okay. So you'd be looking to share that data as they evolve?

I'm sorry, as they what?

To share the data as they evolve with regard to sites of attacks?

Yes, exactly.

Great. And then I think it's -- I mean, you guys did a good job in talking about this, and I think any more emphasis could help to with regard to the number of acute rates and needs for rescue medications, I think, are pretty compelling, especially the way you delineated the charts. So any other perspective, I think, for everyone on the call would be helpful because, obviously, you compared obviously in third trial with regard to lanadelumab, but the fact that you're seeing such reduced rates of attacks and the need for rescue medication, how you might compare and contrast to the field overall?

Yes. Joe, I think -- yes, I think overall, we compare quite favorably, but let me give Chris to give any more detail beyond that.

Yes, I think that's a right -- that's a fair statement. We're seeing so few attacks in the follow-up period. And Joe, I'll remind you, and just everybody here probably knows this already, as well as you, that patients are still encouraged to use rescue medications whenever they have an attack. So to see such a reduction in the use of on-demand therapy is actually surprising. And to see at this degree, I think, is encouraging to the point that we're producing a profound impact on the burden of the disease, and probably significantly decreasing the unmet need for an acute on-demand therapy when 215 is in play. So it's, I think, a bit early to start making general comparisons against some of the other preventatives out there. We'll get more data -- substantial data from Phase III. But we're so encouraged by what we're seeing so far.

I appreciate that. And then just, I guess, a quick logistical question, and thanks for bearing with me. Looking towards the design of the Phase III, obviously, there, I'll put in quotations, "relatively standardized" with regard to the endpoints and what have you. So with that said, do you have something you would consider as of today before talking to the FDA what a potential rate limiting step might be in your design discussions?

Yes. Let me now have Chris answer that question. As we outlined on the slide, we do have in anticipation of what we expect a Q3-month Phase III trial might look like and what a Q6-month Phase III trial might look like. But Chris, anything to add there?

Yes. Joe, nothing in particular comes to mind. It's a really good question. It's one that we've thought a lot about deeply. As you pointed out, the path has been fairly well established. 215 is unique in that it's got such a long half-life and can be given so infrequently. We think standard things will apply here, duration of the treatment period 6 months, the primary endpoint reduction in HAE attacks. We're going to build into this a key secondary endpoint of attack freedom rate. And I think one of the outstanding questions based on the data that we have here today is that you can design a pretty small study to see big efficacy data -- strong efficacy data with low p-values. But we don't yet know how big the safety dataset needs to be. And we have some general ideas based on what's been done by others in the field, but this is a question that we'll ask regulators. I view this as not rate limiting, but certainly a question that we'll ask and get more information about before we finalize the design.

Our next question comes from Sam Slutsky at LifeSci Capital.

Congrats on today's update. Two for me. First, for the ALPHA-STAR study, what are you hoping to learn from the data update next year that we don't already know about STAR-0215? And then any chance that update would impact the Phase III plans at all?

Great. Chris, do you want to talk about that?

Yes. So what we're planning today, Sam, is additional follow-up for the 16 that you've seen here, and that will be mostly in Cohort 3 where we still have some additional follow-up to get to before we have a full 6 months follow-up there. And I expect that those data will not impact our thinking about the Phase III. They might build into our PK model and our PD model and help us finalize the dose selection. But Cohort 2 data so far look like they -- is a compelling dataset that would support the selection of that dose 600, 300 Q3 months as a potential Phase III dose.

Okay. Cool. And then I realize this is a smaller study, but any evidence that lanadelumab is underdosed even at the Q2W frequency? And is there a potential for STAR-0215 to be more effective than lanadelumab based on today's data? Or is kind of the hopes to be in line with Q2W, which is clearly supportive of today's data?

Yes, that's a really interesting question, and it's one that we've asked ourselves. And I think the answer to that is it's dosed just fine. If you look at steady-state concentrations for the Q4 week and for the Q2 week 300-milligram dose levels, efficacy is good, really good with lanadelumab. They're seeing about 85% reduction in monthly attack rates at steady state. The issue with lanadelumab is it takes a good 6-plus weeks to get to steady state. And that's where you see, with lanadelumab's program, attacks happening. And I think that it's not an issue of underdosing, I think it's an issue of how they dose in the beginning. So we've used those data to help inform our program and the design. We've used those data to inform our PK target. And as you know, I think just based on the data that we're seeing today, there's beginning to see evidence that the target that we use based on their dataset might be too high for 215.

So our next question comes from Liisa Bayko at Evercore.

So just a couple of questions from me. First question is, how are you thinking about the initial kind of rollout, you're starting with the Q3-month, and if that makes sense, you get to the market first. Are you thinking that patients will initially transfer to Q3-month or will some hold out for the Q6-month dose? How much of a lag do you think there will be between kind of commercialization of those 2 programs? I'm just trying to kind of understand that dynamic and curious if you've been able to do any work on that.

Yes. Thanks for the question, Liisa. Yes, so our strategy is absolutely to get to market as quickly as we can. And we believe, based on our expectations for what the Phase III program will be, is that the Q3-month gets us there faster than the Q6-month. As you might imagine, we want to make sure that we don't in any way compromise the operations of a Q3-month Phase III. But at the same time, we do want to get the Q6-month trial going as soon as possible. We're currently working through what we believe could be time lines for both of those trials, and we hope to update on that at a future date as we learn more, not only internally from the work we're doing on feasibility, et cetera, but also from regulators. Anything you'd add, Chris?

No, it's great.

Is it fair to assume then that you'd wait for one study to complete enrollment, the Q3-month, before starting the other one, or would you wait a little longer than that? Just trying to understand the time.

Yes. I think Liisa, that is definitely a possibility that we wait to start to enroll the Q6-month once we had secured enrollment in that Q3-month trial. Our plan is get to market as fast as we can with STAR-0215 and start to get patients and physicians comfortable with it.

Okay. And then in terms of like the competitive landscape, there are some products coming out with different mechanisms. You shared a mechanism with lanadelumab. Do you think that will kind of make you a preferential choice with the Q3-month in that initial context? And then, of course, you'll be transitioning to the Q6-month, which really stands out from the kind of rest of the pack, I would say. Just curious how you're thinking about that transition.

Yes, absolutely. We think having a shared mechanism and a shared modality in the form of a monoclonal antibody inhibitor plasma kallikrein with the market leader, TAKHZYRO, lanadelumab, really, we believe, is an advantage for STAR-0215. Patients have comfort in how it controls their attacks. Physicians have comfort in prescribing it and with that mechanism and that modality. So we think that's an advantage for us with STAR-0215. And I think for us, getting to market as quickly as we can with the Q3-month makes sense. I think then there will be patients who will want to dose less frequently, and that's why advancing a Q6-month ultimately makes sense to us, and we'll have to -- we're going to be learning more about that dynamic and where the patient interest is over the coming years as we push forward.

Okay. Great. And then just a different topic, I wanted to just ask a little bit about a question I raised in my note this morning, which is just making that translation between an open-label study to a placebo-controlled study, would we -- just I guess, based on historicals, like what good comps are there out there? What kind of a discount do you think there might be from having a placebo-controlled Phase III? And I mean, honestly, given you're well above the 12-microgram level, I don't see -- there's probably not going to be that much additional breakthrough. But just curious on how you kind of think about that translation.

Yes. Thanks for the question. Yes, and we certainly, as we designed the ALPHA-STAR trial, we gave a lot of thought to that. And I'll let Chris address it.

Yes, Liisa, it's a really important question. And absolutely, we did our homework before designing the study. We looked at every program in the preventative space and asked the question, what does change from baseline result look like compared to versus placebo? And the answer is, when you do the analysis, it's the same. This is an objective disease. Patients have objective attacks. You can't have a subjective influence on attacks in this particular disease. So when you look at the change from baseline values and all the reported studies, we get very similar results to -- versus placebo. So we don't expect a discount as we move into Phase III. We expect that these data today are going to be informative for what we expect to see in Phase III.

Our next question comes from Kelly Shi at Jefferies.

Congrats on the great result. Just curious, for the future label mentioned for every 6 months, you planned 60 patients for the trial. Curious, is this based on FDA feedback? Or we could expect some flexibility on this enrollment target?

Yes. So our -- we certainly have more work to do to flesh out the plan for the Q6-month in terms of size of trial, et cetera. And we expect that, that trial could be smaller in size. A large part of the number of patients going into the Phase III program are supporting the long term, the safety database that we'll need. And so by starting with Q3 months, we expect that trial will want to have a larger patient number in the trial and hope that for the Q6-month, we could go with a smaller patient number. The signal here is strong, and with small patient numbers, we can get to the results we want to see. But certainly, we have to support that with a safety database that will be sufficient for a filing.

Okay. Great. Also I have a question on the data front. On Slide 14, so patient at baseline characteristics seems different in terms of severity of HAE attacks. Acknowledge this is a very small sample size. But curious your thoughts on the impact on the attack reduction based on different attack severity level. So should we expect like a more severe and a better treatment outcome or the opposite? So what kind of variability we could expect in the Phase III in a larger trial, if the severity of HAE attack increased, especially for Cohort 3?

Yes, it's a great question. So the data from our Phase III programs, which is going to be the most informative on this are a little bit more [ keen ] on that answer that is that severe and mild attacks reduce universally without their directionality as to preference for the therapy. So the data that we're showing on Slide 14, to us, tell us that this is effective. We have good reduction in moderate and severe attacks, even when the number of moderate attacks appears to be lower compared within the different cohorts. And it's not something that we're significantly worried about as we move forward into Phase III.

So our next question comes from Michael Higgins at Ladenburg.

Congratulations from us as well on your data. Assuming approval, would you consider a label expansion to younger patients? Any other label changes? And what are your plans outside the U.S.?

Yes. Thanks for the question, Michael. So yes, ultimately, we want to be able to bring STAR-0215 to all patients and would anticipate going to younger ages over time. And Chris, anything to add there from a label expansion perspective across the patient populations?

Just that the need is obvious and that we do intend to address it.

And then I'll let Andrea comment on...

Great. So yes, we plan to commercialize ourselves in the United States, and we're evaluating our plans for commercialization and strategy outside of the U.S.

Sounds good. And one follow-up. What are the gating factors to starting the Phase III in Q1 '25? Any possibility to starting by year-end?

Yes. We -- now with this data in hand, obviously, that has enabled us to take the next step in our Phase III plans. And getting in front of regulators is one of those key steps. And so we're in the process of doing that now. And we're going to do everything in our power to get this Phase III started as quickly as we can.

So from a manufacturing side, that shouldn't be a rate limiting factor?

We don't believe any of our manufacturing is rate limiting at this point.

So our final question comes from Fanyi Zhong at Oppenheimer.

Congrats on the data readouts. This is Fanyi Zhong on for Hartaj. So we have a couple of questions. One is some patients with attack-free from ALPHA-STAR Phase Ib/II through 3 months of follow-up. So will we expect more attack-free data through 6 months of follow-up?

Yes. Yes, Fanyi, that is absolutely our intention. As we get those additional data, we'll certainly provide more, and that could be part of our data update coming out for this group of patients. They're still in follow-up. And as you know, these participants do get to roll over into ALPHA-SOLAR, so we get to continue giving the drug every 3 months and every 6 months, and we'll continue to assess attack-free rate beyond just the 6-month time point.

Perfect. One more follow-up. Will you possibly plan small like head-to-head trial with the lanadelumab in Phase III?

Yes, I can answer that, too, Fanyi. This -- no, not at this point. We don't feel the need to -- I think that it could cause some problems in the design. Lanadelumab would have to be given once every 2 weeks. And that means the controlled [indiscernible] the STAR-0215 group, but also have to get injections once every 2 weeks, and that's just not something that we want to do for our patients. We don't think it's required for registration purposes. I'm not ruling out the possibility at some point of doing some sort of comparison against lanadelumab or understanding switch from lanadelumab. But for supporting registration, we don't believe a comparison head-to-head with lana is necessary.

So this concludes today's question-and-answer session. I'll now turn it back over to Liz for closing remarks.

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.