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

Good morning, and welcome to the Astria Therapeutics 2022 Quarter 4 and Full Year Financial Results and Business Update Conference Call. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Astria Therapeutics website for 90 days following the conclusion of the event. I'd now like to turn the call over to Andrea Matthews, Senior Vice President of Corporate Affairs at Astria Therapeutics. Please go ahead, Andrea.

Thank you, operator. Welcome to today's Astria Therapeutics conference call, where we will provide a corporate update and review our fourth quarter and full year 2022 financial results. With me today are Jill Milne, Chief Executive Officer; Andy Nichols, Chief Scientific Officer; Andrew Komjathy, Chief Commercial Officer; Chris Morabito, Chief Medical Officer; and Noah Clauser, Chief Financial Officer. We issued a press release this morning summarizing our corporate update and our Q4 full year 2022 financial results, which we will reference on today's call and is available on our website. We are also using slides during today's call that are available within the Events and Presentations section of the Investors part of our website. I would like to note that during today's call, as mentioned on Slide 2, we will make forward-looking statements related to our business based on current and future expectations that may be considered -- sorry, actual results may differ from those indicated including those discussed in our most recent annual report on Form 10-K as well as discussions of potential risks, uncertainties and other important factors in subsequent SEC filings, which will be available on our website. Such statements represent our judgment as of today, and Astria undertakes no obligation to publicly update any forward-looking statements, except as required by law. With that, let me pass the call over to Jill, who will provide our corporate update. Andrew will discuss the HAE market opportunity. Chris will go through the Phase Ia safety and PK results and the ALPHA-STAR trial, and Andy will discuss the PD data. Noah will follow with the financial update. Jill will then wrap things up. Jill?

Thank you, Andrea. Good morning, everyone, and thank you for joining us on today's call. Starting on Slide 3. At Astria, patients are our guiding stars. We were fortunate to be able to hear firsthand from patients living with HAE about their experiences with the disease and their hopes for the future during our first-ever STAR-0215 day last month, as you might expect, on February 15. Jasmine shown here shared with us her hope to live a life without the burden of frequently administered treatment. Our goal is to fulfill her vision with a product like STAR-0215. Moving to Slide 4. Jasmines hopes echo what we have heard from the HAE community, the desire to live without limitations from their symptoms and treatments. Our vision for STAR-0215 is to become the first choice preventative treatment for HAE with administration every 3 or 6 months with the goal of normalizing the lives of people living with HAE like Jasmine. We believe that by reducing both treatment and disease burden, we can allow patients to focus their time and energy on what matters most to them. Turning to Slide 5. Here is our planned STAR-0215 early development strategy to execute on this vision. We believe that the HAE treatment paradigm can be transformed with a highly effective, every 3-month preventative treatment like our target profile for STAR-0215. We were able to check the first box here regarding safety, PK and PD in healthy subjects with the positive results from the Phase Ia trial. We will go into more detail about these results today. We also see strong interest in a treatment with this profile from both patients and physicians. Currently, we are evaluating the safety and efficacy of STAR-0215 in HAE patients with our ongoing Phase Ib/II ALPHA-STAR trial and expect proof-of-concept results in mid-2024. Chris will discuss this trial in more detail. Turning to the right-hand side of this slide. We are also exploring a 6-month dosing interval for STAR-0215 as potential additional option for patients. Additional cohorts in the Phase Ia trial are assessing 6-month dosing. Initial results are expected in the fourth quarter of this year. The ALPHA-STAR trial design includes the opportunity to gain initial information on 6-month safety and efficacy in HAE patients, and we are learning more about patient and physician interest in a product with this potential profile. Moving on to Slide 6. 2022 was a pivotal year for Astria, as we progressed our mission to bring life-changing therapies to patients and families impacted by HAE and rare and niche allergic and immunological diseases. Here are the 3 main points that I would like to emphasize for today's call. We brought STAR-0215 into the clinic and shared positive results from our Phase Ia clinical trial in December. The Phase Ib/II ALPHA-STAR trial in people living with HAE is underway with initial proof-of-concept results expected in mid-2024. Additionally, we are well funded to achieve our goals with the closing of an underwritten offering of common stock with gross proceeds of approximately $115 million in December, bringing our expected cash runway through the first half of 2025 based on our current operating plan. I will now hand the call over to Andrew to talk about the market opportunity. Andrew?

So as shown on Slide 7, the HAE treatment market is substantial and it's growing. The global HAE market was well over $2 million in 2022 and is expected to grow to $4.2 billion by 2028. This growth is expected to be driven by patients being diagnosed earlier, more patients opting for treatments to prevent HAE attacks and the expansion of available therapies in more geographic regions. While there are several preventative treatments currently available and in development, we believe that the profile of STAR-0215 as an effective monoclonal antibody plasma kallikrein inhibitor dosed every 3 months or less frequently can address the unmet need in this market and become a leading treatment option for HAE patients. Turning to Slide 8. We recently completed a quantitative market research study with over 100 HAE patients, where we asked them their willingness to try a product profile like STAR-0215. As you can see on the graph to the left, all surveyed patients indicated that they were willing to try a product with this profile, and close to 70% being very willing to either start or switch to a product with this profile. These results include patients either on ORLADEYO, the only current oral treatment available and those on a monthly dosing regimen of TAKHZYRO, also known as lanadelumab and the current market leader, although most patients are on the every 2-week regimen. We've also conducted research with HAE prescribers, who also expressed a very strong willingness to prescribe the treatment with STAR-0215's potential profile and suggest that STAR-0215 would gain strong patient share in a future HAE market, and that's what really excites us with bringing this treatment to the HAE community. I'll then now hand it over to Andy to speak about STAR-0215's profile. Andy?

Thanks, Andrew, and good morning, everyone. So turning to Slide 9. STAR-0215 was designed with the vision of normalizing the lives of people living with HAE. The goals of our program are twofold: first, to generate a high-potency antibody that could inhibit plasma kallikrein to the same levels as lanadelumab; 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 even less frequently. We've demonstrated that STAR-0215 allosterically binds to a unique cytoplasmic kallikrein to produce potent and selective inhibition of plasma kallikrein activity. STAR-0215 includes YTE modifications in the Fc domain specifically to extend its half-life. The high concentration of our formulation and lack of citric acid enables patient-friendly subcutaneous dosing of STAR-0215 with the goal of significantly less injection site pain to patients compared with lanadelumab. I'll now hand it over to Chris to go through the Phase Ia clinical trial. Chris?

Thanks, Andy, and good morning, everyone. Moving to Slide 10. We are pleased to review initial data from the Phase Ia trial of STAR-0215 that were recently presented at the [ Quadi ] meeting in February of this year. This is a randomized, double-blind, placebo-controlled trial of single ascending doses in healthy adult subjects. We have results from the first 3 cohorts through 3 months of the approximately 8-month total follow-up. We have added 2 additional cohorts to the Phase Ia trial in healthy subjects to explore the potential of administering STAR-0215 every 6 months. Cohorts 4 and 5 have single doses of 1,200 milligram subcutaneous at 600 milligrams IV, respectively. Initial results from these additional cohorts and final results from the first 3 cohorts are expected in the fourth quarter of this year. Turning to Slide 11. These initial 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, 7 receiving STAR-0215 and 1 receiving placebo. 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, all in subjects receiving STAR-0215. The most common injection site reaction was injection site redness. There were no reports of injection-associated pain. As noted, these were all mild and resolved without sequelae. For perspective, the most commonly reported adverse reactions associated with lanadelumab are injection site reactions, most commonly pain, upper respiratory tract infection and headache. More than half a lanadelumab-treated subjects reported injection site reactions with administrations during the Phase III trial. Lastly, no treatment-emergent antidrug antibodies were detected with STAR-0215. Let's move on now to pharmacokinetic data. Shown on Slide 12 are the initial STAR-0215 concentrations over 84 days for the first 3 cohorts 100 milligram, 300 milligram and 600 milligram given onetime subcutaneously. Note that the profile show rapid and sustained concentrations over time after single subcutaneous doses and that the concentrations are proportional to dose. You can see visually that the elimination phase is long. This long elimination phase is a result of the YTE modification, which is designed to prolong half-life by slowing down drug clearance. Based on these data, the estimated half-life of STAR-0215 is up to 117 days. Importantly, the 300-milligram and 600-milligram profiles showed durable concentrations at and above levels we believe to be consistent with clinical benefit for at least 3 months. Andy will now walk through our pharmacodynamic data that support this, with results consistent with levels associated with clinical benefit. Andy?

Thanks, Chris. So on Slide 13, you can see that we assess the pharmacodynamic activity of STAR-0215 by measuring the functional inhibition of plasma kallikrein using assays that are similar to those used by Dyax in the Phase I trial of lanadelumab in healthy volunteers and which allowed them to predict doses that would be effective in reducing HAE attacks. In healthy adult subjects, plasma kallikrein levels are very low. So in order to mimic what happens during an HAE attack, we stimulated the production of plasma kallikrein ex vivo by adding factor XIIa to samples taken from the subjects before at various time points after dosing. The plasma kallikrein that is produced clears its natural substrate high molecular weight kininogen that is present in the plasma. And we use the Western blot assay technique to measure this cleavage of high molecular weight kininogen. As a reminder using this technique, lanadelumab at 3 milligrams per kilogram or approximately 250 milligrams, produced about a 50% reduction in factor XIIa activated clean high molecular weight kininogen in healthy volunteers. In addition, we've also assessed the inhibition of plasma kallikrein activity using a peptide substrate reporter assay, in which we look at the cleavage of a small 3-amino acid peptide that we add to the plasma. Using this assay format, lanadelumab had the approximately 250-milligram dose in healthy volunteers inhibited factor XIIa activated plasma kallikrein activity by about 40%. And this effect was lost 40 days after dosing. On Slide 14, we show that STAR-0215 inhibited plasma kallikrein activity by 40% to 60% in both assay formats out through day 84 for the 300- and 600-milligram doses. The magnitude of this effect in both assays is similar to that produced by lanadelumab in healthy subjects. But consistent with STAR-0215's long half-life, the effect is sustained for a substantially longer period of time compared with lanadelumab. Importantly, the level of activity observed to STAR-0215 is consistent with the level of inhibition of plasma kallikrein shown to prevent HAE attacks with lanadelumab. I'll now hand it back to Chris to review the design of our ongoing clinical trial in HAE patients. Chris?

Outlined on Slide 15, ALPHA-STAR is a dose-ranging proof-of-concept trial assessing the potential effectiveness of STAR-0215 in long-term prevention of HAE attacks. This trial is assessing the effects of single and multiple doses of STAR-0215 in people living with HAE due to C1 inhibitor deficiency. As a dose-ranging proof-of-concept trial, the results, if positive, would show robust and durable protection against HAE attacks and inform our dose regimens that may be tested in future trials. All qualifying participants will receive STAR-0215. Initial proof-of-concept data are expected in mid-2024. As shown here, we are planning to amend the trial to add a new cohort labeled here as cohort 3 that would assess the effects of a subcutaneous dose regimen that targets high initial concentrations of STAR-0215, and that we anticipate would maintain plasma kallikrein inhibitory concentrations consistent with clinical benefit for 6 months. Results from this cohort, if positive, would assist in dose selection of STAR-0215 for a potential administration every 6 months. The other 2 cohorts will remain the same with the exception that part of the sample size from cohort 2 will be reallocated to cohort 3. While they continue to target enrolling up to 18 subjects, we plan to add flexibility to enroll more participants to cohorts if needed. Cohort 1 remains a single-dose cohort, administering 450 milligrams once in people with HAE and following for clinical effects out through 6 months. Cohort 2 was a multiple dose cohort testing a loading dose of 600 milligrams followed by a maintenance dose of 300 milligrams given 3 months later, and participants are followed through 6 months after the 300-milligram dose. We anticipate that the effects on HAE attack reduction in people enrolled in these first 2 cohorts may last for 3 months or longer. The cohort 3 has 2 initial 600-milligram doses given 1 month apart with participants in follow-up for 6 months after the second dose. Given the PK and PD profile demonstrated in healthy human subjects, it's possible that the clinical results from a dose regimen that targets these anticipated concentrations may endure for 6 months. The endpoints for the trial, including safety, attack rate changes, PK and PD remain the same. So far, the trial has initiated in the U.S. and Canada, and we're actively bringing patients into the trial, and we're on track to initiate in Europe, including the U.K. midyear, assuming receipt of regulatory approvals. Data are expected in mid-2024 and are anticipated to include initial results from all 3 cohorts. The goal is to show a significant reduction in HAE attacks following STAR-0215 treatment. We expect these data, if positive, will help us refine our approach to establishing the effectiveness of STAR-0215 as a long-term preventative against HAE attacks and bring us towards our goal of normalizing the lives of people living with HAE. Finally, we show on the slide the planned long-term open-label trial. This trial is anticipated to enroll participants from STAR -- from ALPHA-STAR and is expected to start later this year in time for the initial completers of the ALPHA-STAR trial to enroll. We expect this trial to evaluate primarily safety as well as effects on HAE attack and quality of life. I will now turn it over to Noah to provide a financial update. Noah?

Thanks, Chris, and good morning, everyone. Turning to Slide 16, I'll provide a brief summary of important financial information. In December 2022, we closed a $115 million underwritten offering of common stock. As of December 31, 2022, we had cash, cash equivalents and short-term investments of $226.4 million compared to $116.6 million as of September 30. We expect that our cash, cash equivalents and short-term investments are sufficient to fund our current operating plan through the first half of 2025. Our net loss was $13.3 million for the fourth quarter of 2022 or $0.72 per share and $51.8 million for the full year 2022 or $3.55 per share. As of December 31, we had approximately 27.5 million common shares outstanding and approximately 33.2 million common equivalent shares outstanding when including our outstanding convertible preferred shares on an as-converted basis. For additional financial information, please see our earnings press release and our 10-K, which we plan to file with the SEC after market today. Jill will now review our upcoming milestones and then open the call for questions. Jill?

Thank you, Noah. In summary, on Slide 17, we are thrilled that STAR-0215 has shown early proof of concept in the Phase Ia trial for its target profile, a long-acting preventative therapy for HAE, a best-in-class PK profile and dosing every 3 months or less frequently. We also believe there could be an opportunity to dose STAR-0215 every 6 months, and we are evaluating this with cohorts added to our ongoing Phase Ia and ALPHA-STAR trials. Looking to our upcoming milestones, we expect preliminary results from the additional cohorts in healthy subjects as well as the final results from cohorts 1 through 3 in the fourth quarter of this year. As Chris reviewed, the ALPHA-STAR trial in HAE patients is underway with initial results expected in mid-2024 from single- and multiple-dose cohorts, including the planned third cohort. Additionally, we will plan to initiate a long-term open-label trial in the second half of this year. As we think about the future, we are excited about the potential for STAR-0215 to provide long-acting effective attack prevention for people living with HAE. Turning to Slide 18. Here, we see Jasmine again, this time with Kim, Melissa and Melissa's daughter Hannah, all living with HAE, from when they joined us at our offices last month. Speaking with the HAE patient community to better understand their lives and needs guides all that we do in Astria, and we are so thankful to Jasmine, Kim, Melissa and Hannah for sharing their experiences with us. We are charting a new path for HAE patients, one that envisions an opportunity for a better quality of life with a long-acting preventative therapy that has meaningful efficacy with infrequent dosing and could fulfill the vision of normalcy that these 4 patients express. Lastly, on Slide 19, to recap, 2022 was a pivotal year for Astria as we progressed STAR-0215 into the clinic and shared positive results from our Phase Ia clinical trial in December. The Phase Ib/II ALPHA-STAR trial is enrolling HAE patients, and we anticipate proof-of-concept results in mid-2024. We are well funded to achieve our goals with anticipated cash runway through the first half of 2025 based on our current operating plan. We are well positioned to execute on our development plans for STAR-0215, as we aim to allow patients to focus their time and energy on what matters most to them. With that, I'll ask the operator to open up the call for your questions. Operator, can you please repeat the instructions and poll for questions? Thank you.

[Operator Instructions] So our first question comes from Hartaj Singh from Oppenheimer.

Great. I've got a couple of questions. So I'll just ask one. They're a little different. So I'll just ask one and then follow up with the second one. You talked about the YTE modification to the antibody and then lack of citrate. So is it kind of getting into extended follow-up with patients? So I just want to ask Andy about historically have YTE modifications over the long term produced some side effects that you're watching out for? Just anything untoward or not? And again, great presentation on all the data, which I didn't say earlier.

Thanks, Hartaj. So about the YTE modified antibodies that have been studied in the clinic, there have been no specific reports of any safety issues associated with the YTE. I recall it has actually been studied quite extensively in the context of nirsevimab, the anti-RSV antibody that is used in neonates for the prevention of RSV infection during the RSV season, so in other words, to provide 6 months of coverage; and also in the every shelf product, which contains 2 YTE-modified antibodies for prevention of COVID-19 in high-risk individuals. And there has been no reported safety issues associated with those antibodies that would lead us to have any concerns about the YTE specifically.

Great. And then I got a question just on the commercial side. What we're hearing from companies that we cover and then just others is that, suddenly the HAE market is kind of shifting over to a prophylaxis market. It used to be less than 50% prophylaxis and now it's getting close to sort of 2/3 prophylaxis and could increase even to maybe 80%. And then with the orals being introduced, there are more and more patients potentially taking -- being on medication. How do you see in the future 0215? I know it's early days. Do you really think it's more -- competes against other injectables? Or do you think the orals, which are -- still looks like once a day and probably will stay there that -- that they will be fair games also assuming that 3-month profile, maybe even up to 6 months?

I can take that. So a couple of comments. You're absolutely right, the preventative market in the U.S., about 2/3 of patients are on a preventative treatment. That percentage is slightly lower or lower in Europe, closer to 40%, 45%. So we do believe that the market will continue to grow with the emergence of new treatments. However, as I mentioned earlier in the presentation, we're really excited about the profile of STAR-0215 and the potential of being an effective treatment but also one that reduces that burden of treatment. And 100% of the patients that we surveyed expressed the willingness to either try the product, so those were patients that were currently not on treatment or switched to that treatment. And then the subgroups of patients, those that were either ORLADEYO or those that were on a monthly treatment of TAKHZYRO, 100% of those patients expressed an interest in switching to those treatments. So we do believe that the market will continue to grow, but also, we believe that given the profile of STAR-0215, that we'll be able to successfully switch -- transition patients from either orals or other injectables onto STAR-0215.

Great. Andy, and actually -- I'm sorry, I apologize. I have one follow-up question, and I apologize for this. Maybe just a little bit of a shout out to Noah. We noticed that your fourth quarter spend was lower than what we expected, and we've been kind of being more cautious in our outlook for spend by small-cap biotechs. Noah, if you can just talk a little bit about how you see the progression of your OpEx through the rest of the year.

Hartaj, I think I'd point you to our runway guidance, which is that our current cash supports us through all of the first half of 2025 with the understanding that we do expect to have sort of a gradual ramp along the way. So I think, without getting into too many specifics about quarter-over-quarter expense, I think a gradual ramp as we ramp up clinical activities is the right way to think about it.

Our next question comes from Oliver McCammon from LifeSci Capital.

This is Oliver McCammon filling in for Sam Slutsky. Just one question from me. For the ongoing Phase I study in healthy volunteers, how might the data from the 1,200 milligram subcutaneous and 600 milligram IV cohorts impact your strategy on the future clinical development of 0215 versus what is already known from the prior cohorts?

Oliver, this is Chris. Thanks for the question, and it's an important one. The data that we've obtained so far are compelling and suggests that we have the capability with this molecule to achieve a profile that could target every 6 months administration in people, sufficient enough to prevent attacks in a meaningful way. We have a half-life now that's about 4 months long, and we have no evidence so far of safety signals that would give us pause. What we are doing with these additional cohorts is asking the question can higher concentrations maintain STAR-0215 -- higher initial concentrations maintain STAR-0215 over 6 months above that critical threshold, which we think is 12 micrograms per ml or 80 nanomoles associated with robust target engagement and strong pharmacodynamic activity. We're also asking the question how well tolerated is administrations of STAR-0215 to achieve these kinds of concentrations. Based on what we've seen so far, I believe we do not need to go up to 1,200 milligrams to achieve a profile that would be -- that would allow for 6-month administration, but this subject in healthy volunteers will give us the upper limit that we can stretch to as we think about how to do so.

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

Thanks for the questions, and thanks for a very efficient call. So just a couple of questions on ALPHA-STAR. So first, as the HAE market grows and it's getting a little more crowded slowly with the new therapies and therapies that are growing, how do you view -- I mean, it's not a big study, but how do you view additional trials and competition for patients to start with?

So what we thought deeply about this as we designed ALPHA-STAR. The operational risk, I think, is an important line that we've considered as we thought about the design and, obviously, about how we're executing the trial. One important element that we consider when talking to physicians and the patients is that there is now wide access to medicines that have the potential to be effective. There's also access to additional trials. How could we design this in a way that would allow patients to feel comfort that they're going to get something out of it? So we eliminated the placebo group, and we've done so using strong science to support the data integrity that we'll get from this. And that simple act of eliminating the placebo group has resounded favorably in the community, and optimistically, that will allow for some people who were hesitant to enter a trial in which, for up to 9 months, they would not receive anything but their on-demand therapy are now thinking about this trial. We've also been working incredibly closely with the HAE physician and patient community. This space is fortunate in that the advocacy organization that is based in the U.S. with outreaches throughout the world through the HAEi is very strong, has an active community, works well with us as a partner and is helping us think about how to operationalize the study in a way that makes sense for people living with this disease. We've been working with the physician community to understand how best to talk with the community about their participation. And the final point is that it's a global trial with a big footprint. We have -- I think we've now been pretty open about this. We have lots of sites that we're targeting to participate in this trial. And we hope that even if [ we ] find just one patient to potentially participate that we'll be able to enroll this in a way that meets our operational guidelines.

That's very helpful. And I guess when you look at these -- the data you have and the plan that you have for ALPHA-STAR and the long-term dosing intervals, how do you look to present the data and also the potential impact on any statistics you're looking at with the potential or anticipated -- albeit small anticipated needs for the rescue meds?

Yes. So what we anticipate is that we'll have proof-of-concept data in mid-2024, and that will include the initial data from all 3 of these cohorts. So those initial data would be able to communicate what we think would be meaningful for the community. And what we would like to be able to show is that the profile is -- from a safety perspective, is favorable that there aren't any additional or unexpected safety findings, that we have robust, durable reduction in attacks, in this case measured from baseline -- change from baseline and attack frequency, that we have PK and PD that's supportive of the clinical and safety findings that we've been describing and that we have a meaningful and positive impact on quality of life. This is a disease -- and as you know, from other trials, so this is a disease that in proof-of-concept trials using a small sample size that allows for a demonstrably meaningful representation of data. Typically, in Phase Ib/II trials in the space, cohorts are about 4 to 7 subjects, and that's exactly where we anticipate being here with the option to add more if we need to. The reason for that is that we anticipate a very large effect size. Lanadelumab, garadacimab in Phase III are showing about 85% reduction compared to placebo. That size in terms of change from baseline allows for a smaller overall sample size. So even with this few number of subjects in each cohort, we anticipate being able to demonstrate that this has the potential for meaningful effects of patients.

Our next question comes from Eun Yang from Jefferies.

This is Eun. Can you hear me okay?

Yes, we can.

So the probable concept data that we are expecting mid of next year. So you mentioned the all 3 cohort. So how many months of follow-up are we expecting when we see the data? And then second question is the -- you mentioned it's a safety tolerability PK/PD changes in PD rate. Because it's a single dose, we are not going to see -- almost certainly, we are not going to see a ped 3 rates in this study, correct?

Yes. Thanks for these questions. So in terms of data, we are anticipating proof-of-concept data in mid-2024. The proof-of-concept data should be able to demonstrate that we are in target to achieve our target profile, which, as you know, is reducing effects when given every 3 months or potentially every 6 months. So while I can't guide you today to what we anticipate showing in mid-24, I could tell you that we're looking to be able to show data that would support that kind of profile. Regarding your question about endpoints, the proportion of people who are attack-free is a meaningful and important endpoint. It is possible that with this profile, given its PK curve, and as you know now, the PD effects are through at least 84 days, that we can show a substantial people -- number of people that have no attacks compared to baseline. And if we do have compelling data, meaning high integrity data that are capable of showing that, we would be pleased to be able to show that.

Yes, I have one more follow-up. So clinical sites in the U.S. and Canada are up and running. It sounds like the patients have been enrolled as we speak. And then European sites to open maybe this year. When you enroll patients, do you have to enroll in sequential from cohort 1, 2, 3? Or can you actually enroll patients simultaneously across [ a pretty ] different cohort?

Right. So with the protocol as written calls for a safety check before we start cohort 2. That's the one requirement that's in the protocol so far. Beyond that, it is possible that we can enroll one and not completely fill it before we start the other. At this point, we anticipate not enrolling all 3 at the same time for a variety of reasons, the most important thing just the accumulation of data. So while -- the answer to your question is mixed. We don't have to go exactly through each one to start the next but we are staggering the start of cohort 2.

Do you have a kind of a ratio in terms of number of patients who are being enrolled in the U.S., Canada versus Europe?

I don't.

So our next question comes from Michael Higgins from Ladenburg.

A question on the cohorts in Phase Ia. Are there triggers for adding cohorts in ALPHA-STAR? If you can share those with us, we'd appreciate it.

Michael, could you maybe clarify your question, the Phase Ia data to trigger ALPHA-STAR?

Yes. No. In Phase Ia, there were additional cohorts added obviously from the first 3 to the next 2. I'm wondering if there are any triggers to add additional cohorts in ALPHA-STAR?

So we have added the possibility to add cohorts to ALPHA-STAR. Actually, that's been sort of in our mind from the beginning. We've done that now with adding cohort 3 to test the feasibility of a regimen that could achieve the potential for every 6 months dosing. There aren't any a priori defined triggers for additional cohorts. However, if evolving data from our trial or from the Phase I show that there might be additional questions to ask, we do have that possibility.

Okay. And then one follow-up. Are you doing anything in the current trials or potentially future trials to reduce injection site reactions? Hasn't been a major issue so far, but curious of your thoughts there.

Yes. So yes, we're fortunate that the injection site reaction data are very reassuring so far. We've had a few, they've been mild. The most common one is just redness, which is fairly common when you inject anything under your skin. So, so far, it is comforting to know that there's nothing here that makes us concerned about moving forward. The formulation right now is 150 milligrams per ml, which is standard for a subcutaneously administered monoclonal antibody. There may be opportunities to concentrate that a bit more to allow for less volume that could potentially decrease the frequency of injection site reactions. And that's work that's ongoing, and we'll certainly be able to fill you in and the community in about that as those efforts continue.

I'll get one more in here. I have a question on the IV. If you could review for us your rationale for testing an IV, the 600 milligrams in the Phase Ia again.

Sure. So there's 2 main. One is that 600 milligrams IV will provide a very high concentration. And what we're more concerned about in the Phase Ia data is the effect of the concentration than anything else. And that will allow us to -- the ability to get to a high concentration and watch the PK profile, PD profile, ultimately, safety profile over time, over the full 8 months of follow-up. The second is that we have some additional questions regarding bioavailability and absorption that, comparing the IV -- 600 milligrams IV to the 600 milligram subcutaneous dose would help us answer.

This concludes our question-and-answer session. I'll now turn the call back over to Jill.

Thank you, Tara. Thank you all for joining our call this morning and for your continued support of Astria. We'll keep you updated as we execute on our STAR-0215 program, the ALPHA-STAR trial and share other areas of progress in the company. We look forward to speaking with you again. 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.