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

Good morning, and welcome to the Astria Therapeutics webinar. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Astria Therapeutics website following the conclusion of the event. I would now like to turn the call over to your host, Elizabeth Higgins with Astria Therapeutics. Please go ahead.

Thank you, Sarah. Welcome to today's Astria Therapeutics STAR-0310 Conference Call. With me today are Jill Milne, Chief Executive Officer; Christopher Morabito, Chief Medical Officer; Andrea Matthews, Chief Business Officer; Andrew Komjathy, Chief Commercial Officer; and available for questions, Noah Clauser, Chief Financial Officer. We issued a press release yesterday announcing that we have matured into an exclusive worldwide license agreement with Ichnos Sciences for an OX40 portfolio to be developed for the treatment of atopic dermatitis. 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 event, 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. I will now pass the call over to Jill, Chief Executive Officer. Jill?

Thank you for joining our update call today. We're excited to tell you about our licensing deal with Ichnos Sciences, which we believe transforms our pipeline at Astria. A pipeline which now includes both STAR-0215 for the potential treatment of HAE and STAR-0310 for the potential treatment of atopic dermatitis. Let's start in to understand the journey of how we got to where we are today and why we're so excited about the future. Astria was formally launched 2 years ago when we acquired a private biotechnology company and their stealth program in HAE, which I think will transform the treatment landscape for people living with this rare disease. As you well know, finding great assets is challenging, but I think we've done it again. In deep diligence with Ichnos Sciences on its Telazorlimab program, we uncovered a backup program they had in the OX40 space. Ichnos was an innovator in the OX40 space being the first to get to the clinic with their lead telazorlimab anti-OX40 antibody. They showed the OX40 pathway works in atopic dermatitis in 2 Phase II clinical trials. But this is an example of the challenges of being the first mover. Telazorlimab demonstrated favorable clinical results, but its efficacy was not competitive in atopic dermatitis likely due to its low affinity for the OX40 receptor. What we are excited about and why we are here with you today is their preclinical backup program, which we are calling STAR-0310, that has been shown in preclinical studies to have greater than tenfold increase in binding affinity for the OX40 receptor, which importantly has translated into a greater than tenfold higher potency in primary T cell assays. We believe this profile will translate to a potential best-in-class OX40 therapeutic. Chris will tell you more about the differentiated profile and how it stacks up in this space in a few slides. 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 would choose our products because of their strong competitive efficacy, low treatment burden and favorable safety and tolerability profile. Our initial pipeline will continue to be focused on well-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-215 (sic) [ 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. STAR-0310, the reason we are here today is an anti-OX40 antibody that we have in license from Ichnos Sciences and plan to develop as a potential best-in-class therapeutic for atopic dermatitis and potentially other indications. Let's move on to Slide 5, and I can introduce our pipeline. We believe that our focus and approach can be applied to both STAR-0215 and now STAR-0310 in order to improve patient experience and become potential first choice treatments. STAR-0215 is a monoclonal antibody inhibitor of plasma kallikrein, a clinically and commercially validated target in HAE. Our antibody was designed with YTE half-life extension technology which translated to a half-life that we believe will support every 3 months and every 6-month dosing intervals. We see this as a potentially significant benefit for patients. Monoclonal antibodies are a trusted modality in HAE, favored for their safety and tolerability, and they have and efficient regulatory path to BLA. In our healthy subject data, with STAR-0215, we saw a potential best-in-class PK profile with a half-life of up to 117 days, and sustained inhibition of plasma kallikrein during that time. We think there's a strong commercial opportunity for our First Choice preventative in this space. The HAE market is large and growing, estimated to be over $4 billion by 2028. The STAR-0215 program is moving forward with great momentum. We have hit the milestones that give us conviction that we have an important program here, and we believe provides a strong foundation for us to build the pipeline. That brings us to today. We have in-licensed an OX40 portfolio. This portfolio fits with our corporate strategy. It has the potential to make a real difference for patients. It is based on a clinically validated mechanism, and we believe it can be potentially best-in-class among the OX40 programs. OX40 has become an exciting space in immunology and is a key immune regulator that regulates T cell functions. Recent acquisitions of OX40 programs by Amgen and Sanofi were each over $1 billion. We believe that STAR-0310 has the potential to be favorably differentiated from these programs. Targeting this pathway has the potential to treat a range of immune-mediated diseases and inflammatory disorders. We have also applied YTE half-life extension technology to STAR-0310. STAR-0310 has a potential best-in-class profile with high affinity, potential for favorable safety and tolerability profile with low T cell depletion from ADCC or possibly on target cellular toxicity and importantly, we believe less frequent dosing. There is commercial opportunity for STAR-0310 to be potential first choice OX40 treatment for moderate to severe atopic dermatitis. And a market that's estimated to reach $26 billion by 2030 in the U.S. alone. The next slide is an overview of our expected milestones for the integrated pipeline with both programs. With STAR-0215, we are anticipating sharing additional Phase Ia healthy subject results at ACAAI in November. These data are expected to further support the profile of Q3 and Q 6-month dosing with STAR-0215. Our Alpha STAR trial in HAE patients is also on track and progressing well. We are currently enrolling patients in the third and final cohort, and we are on track to share results mid next year. Assuming positive results from this trial, we plan to initiate a single pivotal Phase III in Q1 of 2025. We are actively working on the design of our Phase III trial. As we bring STAR-0310 into our pipeline, we expect to submit the IND by year-end 2024 and to share the preclinical profile of STAR-0310 in 2024 at a scientific conference. We anticipate early proof-of-concept results from a Phase Ia trial in Q3 of 2025, which will be an important milestone for the program. Our goal of this trial will be to establish the target profile we have for STAR-0310 in terms of long half-life, initial PD as well as safety and tolerability. Half-life extension technology has a great track record, and we expect the data from this trial will be able to demonstrate whether it works with STAR-0310 in healthy patients. Next, assuming positive results in the Phase Ia trial, we anticipate initiating a Phase Ib clinical trial in atopic dermatitis patients, in the second half of 2025 and reporting results in Q2 of 2026, with the goal to demonstrate proof of concept in patients. We think STAR-0310 is a great addition to our pipeline. And together with STAR-215 fits well with our corporate strategy and makes us a stronger and more attractive company with a regular cadence of anticipated clinical milestones over the coming years. I will now turn it over to Andrea Matthews, our Chief Business Officer, will introduce the potential opportunity for STAR-0310. Andrea?

Thanks, Jill. Here's an introduction to atopic dermatitis, a chronic disease where current treatment options are not sufficient to address the needs of patients. Atopic dermatitis is an immune disorder associated with loss of skin barrier function and itching and it's caused by diverse T cell-driven mechanisms that include Th2, Th1 and Th17/22 pathology. Approximately 16 million adults in the U.S. are affected and half of these are reported to have moderate or severe disease. Standard of care treatments are steroids and topical medications, which can treat symptoms but do not address the underlying disease. Our goals with STAR-0310 are to reduce disease activity, relapse rate and treatment burden for moderate and severe patients to help normalize their lives. There's a lot of excitement about the atopic dermatitis market. Here's an overview of the U.S. moderate-to-severe treatment market, which is large and anticipated to expand rapidly to $26 billion by 2030. This expansion is expected to be due to an increase in drug treatment rates, especially as new therapies become available and we also anticipate that there will be more patients treated with biologics as dermatologists grow increasingly more familiar and comfortable with them. Overall, this market growth in the U.S. creates a lot of opportunity for a product for the profile like we anticipate for STAR-0310. Here, we take a closer look at the approved and under FDA review biologic for atopic dermatitis Currently, the market is dominated by dupilumab, also known as DUPIXENT, which was launched in 2017 in the U.S. and the sense established in the new standard of care for patients that are not adequately controlled with topical prescription treatments. Dupilumab sales in atopic dermatitis for 2022 in the U.S. are estimated at more than $4.5 billion. Dupilumab is an IL4 receptor alpha monoclonal antibody and that inhibits both IL4 and IL13 and its co-market advice in [indiscernible]. There are also 2 IL13 biologics listed here, tralokinumab, which is also approved and lebrikuzumab, which is under FDA review. All 3 of these therapies target Th2, they're typically administered subcutaneously every 2 to 4 weeks, and based on their efficacy profiles, may not be able to fully address the needs of atopic dermatitis patients. For example, up to 40% of atopic dermatitis patients that tried dupilumab are nonresponders or have an inadequate response. We believe that by targeting OX40, STAR-0310 can address a broader set of T cells. This could provide the potential for better efficacy and broader addressable patient population, including those with an inadequate response to dupilumab. The use of half-life extension technology also sets STAR-0310 apart due to its potential to provide durable efficacy with less frequent dosing every 2 to 3 months. There are 2 OX40 pathway inhibitors in the clinic, and we'll touch on those on the next slide. As a potential long-acting OX40 inhibitor with activity both in and beyond type 2 inflammatory pathways STAR-0310 is well positioned to potentially address the needs for a safe, effective and infrequently administered atopic dermatitis treatment, particularly for those with suboptimal response to dupilumab as well as more broadly. The significant potential of treatments that target the OX40 pathway has been appreciated in 2 recent transactions shown here. In 2021, Amgen entered into a $1.2 billion deal with Kyowa Kirin, for the OX40 antagonist, ractinumab for rights outside of Japan and this include to a $400 million upfront payment, rocatinlimab is currently in Phase III trials for atopic dermatitis. There's a second clinical stage OX40 pathway program and amlitelimab, which targets the ligand and is currently completing a Phase IIb trial in atopic dermatitis. This program was acquired in 2021 by Sanofi in a $1.4 billion acquisition of Kymab. Sanofi also sees the potential of the OX40 pathway beyond atopic dermatitis, and they are currently recruiting an asset trial. We believe that STAR-0310 could potentially have the best profile for an OX40 pathway treatment and are excited to begin work on the program and potentially bring this treatment forward to patients. I'll now turn it over to Chris Morabito, our Chief Medical Officer, who will review STAR-0310's potential in more detail. Chris?

Thanks, Andrea. As I go through the rationale for 0310 being the potential best-in-class and a potential first choice OX40 pathway inhibitor, I'll made 3 major points. First, inhibiting OX40 Pathway has advantages in atopic dermatitis and 0310 has the potential for competitive efficacy. Second, 0310 has potentially the best-in-class dosing and administration profile and third, because of its approach to OX40 pathway inhibition, 0310 may have a favorably differentiated safety and tolerability profile. OX40 is a T-cell regulatory protein that modulates T-cell functions. OX40 has important roles in atopic dermatitis because it impacts inflammatory pathways that cause disease including effector T cell cytokine release, such as IL4 and IL13. But OX40 does much more than regulate T cells that produce IL4 and IL13, which are called Th2 cells. By inhibiting the OX40 pathway, effector Th1 and Th17/22 can be silenced as well as memory T cells, while sparing regulatory T cells. As atopic dermatitis is driven by a broad range of T cell mechanisms, not limited to Th2, which is what anticytokine biologics like dupilumab target. Inhibiting OX40 in AD could potentially lead to more clinical responses and being effective in a broad population of atopic dermatitis patients. So far, a proof of concept that OX40 pathway inhibition may be a safe and effective approach in AD has been shown by telazorlimab from Ichnos, rocatinlimab from Amgen and amlitelimab from Sanofi. We have in-licensed the OX40 antibody portfolio for Ichnos, which started with the first-generation OX40 program called telazorlimab. Telazorlimab demonstrated a proof of concept in a large Phase IIb trial showing efficacy across a broad range of endpoints and a favorable safety profile. As the first generation OX40 inhibitor, telazorlimab had low affinity for OX40, and we believe the efficacy results, while favorable, are limited by slow affinity. We believe we can do better with STAR-0310, which is an affinity mature version of telazorlimab with a YTE modification to prolong its half-life. The 0310 candidate minus the YTE. It's engineered with 99% sequence identity to improve potency without changing the potential for a favorable safety profile. We have engineered 0310 to include the YTE modification of the Fc region in order to increase its half-life. Our initial experiments have shown that STAR-0310 has properties that we think will permit us to administer STAR-0310 once every 2 to 3 months or with less frequent dosing compared to other therapies in clinical development. So now we've established that inhibiting OX40 may be an effective approach to treat atopic dermatitis. Our intention is to develop STAR-0310 as a potential first choice OX40 pathway inhibitor. Amlitelimab currently in Phase IIb is a monoclonal antibody against the 0X40 called OX40L. OX40L is present on an array of cells, including epithelial, endothelial, smooth muscle, mast and B cells. In contrast, OX40 is present only on activated T cells or T cells involved in active inflammation. Rocatinlimab is another OX40 antagonist, and it is in Phase III. Rocatinlimab is an afucosylated monoclonal antibody, which means that it is designed to be cytotoxic in order to silence effector T cells. We'll see later how amlitelimab non-T cell OX40 ligand binding and rocatinlimab afucosylation impact safety and tolerability findings. We anticipate both amlitelimab and rocatinlimab will be administered once every 4 weeks or once monthly, while STAR-0310 with this YTE half-life extension has the potential to be administered once every 2 to 3 months subdued. In vitro and preclinical data support potential for competitive efficacy of 0310. In this graph, we show that a 0310 candidate, which is 0310 minus the YTE modification matches best-in-class potency based on preclinical and in vitro data generated to date. STAR-0310 candidate inhibited donor T cell proliferation in vitro and the results are similar to rocatinlimab with at least tenfold better than telazorlimab. On the right, we are showing that telazorlimab, the first generation of the 0310 candidate showed durable inhibition of Th2, Th1 and Th17/22 PD markers in atopic dermatitis patients in a Phase II trial. These data show multiple full impacts on effector T cell activities that lasted for at least 6 weeks after the last dose, which was given on day 29 in this trial. There some pathologic results from the same trial are shown at the bottom right. Here, telazorlimab treated participants showed resolving AD pathology that also persisted well beyond the last dose administered. The improved affinity of the 0310 candidate is expected to potentially the impact on AD compared to telazorlimab and adding YTE is expected to extend the durable inhibition of T-cell pathogenic AD responses, which goes beyond targeting Th2. Now let's move into data that demonstrate the potential for favorable safety with STAR-0310. Beyond the YTE modification, another major difference between STAR-0310 and rocatinlimab is that the 0310 candidate has lower antibody-dependent cellular cytotoxicity or ADCC, particularly sparing regulatory T cells. ADCC is described on the right side of the slide. It is a process that involves immune-mediated killing of cells expressing the target antigen. It is associated with cytokine release reactions such as fever called pyrexia chills and flu-like illness. Rocatinlimab has enhanced ADCC, and therefore, the potential to complete a range of activated T cells leading to adverse events of limiting the therapeutic window. As we'll see later, rocatinlimab is associated with pyrexia, chills and infection-related side effects. Showing these graphs, the 0310 candidate has low ADCC when a population of donor T cells are tested. Additionally, 0310 further protects regulatory T cells compared to rocatinlimab. This finding may translate to positively differentiated impacts on immuno modulation in disease. Finally, the YTE modification may further reduce ADCC, allowing for the potential for a favorable safety profile. These data plus the potency data on the previous slide suggests that 0310 may impact efficacy while potentially sparing T cells. As I said earlier, the OX40 pathway is clinically validated in atopic dermatitis. On this slide, if we look at amlitelimab or rocatinlimab efficacy results from Phase II trials. Placebo-subtracted efficacy endpoints are shown here for amlitelimab and rocatinlimab. While clinical trial conditions are different, it appears that rocatinlimab assessed in Phase IIb has more positive impacts on AD compared to amlitelimab assessed in Phase IIa. When we look at endpoints that were measured in common, such as change from baseline EASI, 46% versus 31%, EASI-75, 43% versus 34% and EASI-90, 33% versus 20%. Sanofi just recently announced positive Phase IIb results for amlitelimab, which use teams from baseline EASI as a primary endpoint. So far, we know that the IIb results seen in line with the Phase IIa results and we look forward to more data from this trial as they become available. A core element of the attractiveness of this mechanism in atopic dermatitis is that it regulates Th1, Th2 and Th17/22 effector T cell pathways. The added impacts create the potential for broader and more clinically significant efficacy compared to Th2 specific antibodies such as dupilumab in clinical trials, inhibiting OX40 chronically appears to have a more significant impact on AD responses than inhibiting downstream cytokines. After 36 weeks of treatment rocatinlimab achieved higher IGA responder rates than those achieved by 52 weeks with dupilumab in a separate clinical trial. Our goal with 0310 is to have at least a rocatinlimab like efficacy with less frequent administration. We think there is potential for high responder rates with 0310 due to more continuous target engagement and also, as mentioned previously, 0310 is expected to be T cell preserving, which gives the potential for a wider therapeutic window. Our goal is to ensure that 0310 has a favorably differentiated safety profile when compared to other OX40s in development. When we look at rocatinlimab, T cell destruction leads to cytokine release, which can cause pyrexia and chills, increased risk of infection and [indiscernible]. Additionally, amlitelimab and OX40 ligand inhibitor is expressed in a wider array of cell types, and it may increase the risk for upper respiratory infection, nasopharyngitis, respiratory, and vascular adverse events. Because 0310 has the potential to preserve T cells and also has the potential to be more favorably -- have a more favorable safety profile than rocatinlimab. As in turn to the future, and let's review our clinical plans for STAR-0310, we are planning a Phase Ia clinical trial in healthy adult subjects, which we expect to initiate in early 2025. Our goal for this would be to establish early proof of concept for STAR-0310 as a long-acting inhibitor of OX40. The trial is planned to have 3 single ascending doses and will assess safety and durability of PK and PD. We expect initial proof-of-concept results in this early trial in Q3 of 2025. We are also planning a proof-of-concept trial with multiple doses in atopic dermatitis patients to assess clinical impact or EASI of 0310. We are expecting 2 subcutaneous dosing regimens and endpoints that will assess safety, PK, PD and clinical endpoints in patients. The goal is to demonstrate initial efficacy in atopic dermatitis as well as differentiation on ADCC related safety and tolerability compared to rocatinlimab and on-target OX40 ligand binding AEs with amlitelimab, and we expect initial proof of concept results in Q2 of 2026. Based on what we have seen so far and our confidence in 0310s profile, we believe that 0310 could be a best-in-class and first choice treatment for atopic dermatitis. Starting first with common factors for OX40 pathway monoclonal antibodies targeting this pathway as the ability to have disease-modifying impacts. The OX40 pathway has potential effectiveness across AD driven by multiple effector T cell types, not just Th2 and the potential benefit here is robust and sustained responses across a broad range of AD. We also believe that due to the YTE modification, long-acting 0310 has the potential to be administered 4 to 6 times per year compared to the anticipated 12 times per year for amlitelimab and rocatinlimab and we believe the safety profile of 0310 will differentiate from both rocatinlimab and amlitelimab as STAR-0310 has the potential for reduced T cell depletion due to ADCC and limited potential for AEs due to off-target binding. Beyond atopic dermatitis, we believe that targeting OX40 has strong potential in a broad range of additional indications where there remains need to normalize patients' lives with new therapies that are long-acting, effective and safe. We are also planning on exploring the potential for 0310 in asthma, chronic urticaria and/or other autoimmune indications, and we look forward to sharing preclinical results in additional indications in the second half of 2024. We would now like to turn to our HAE program and our Chief Business Officer, Andrew Komjathy, will provide an introduction to STAR-0215.

Thanks, Chris. So our STAR-0215 program is the potential first choice treatment for the prevention of attacks in hereditary angioedema. HAE is a life-threatening and life-changing disease characterized by severe unpredictable, painful and sometimes life-threatening edema in the skin, abdomen and airway. For most patients, it's caused by deficiency in a protein called C1 inhibitor, which is an important component of the body's contact pathway. Patients with HAE live in fear of having an attack that could be immensely painful or leave them disfigure for several days or worse proved to be fatal. There are approximately 8,000 people affected in the U.S. and approximately 15,000 in the EU. The standard of care for HAE has evolved from only on-demand treatments and respond to attacks to include both on-demand and preventative treatments. Our market research shows that there is a strong interest in a product with the potential profile of STAR-0215 in the HAE market from both the patient and physician perspective. And let's turn to more details on this. The HAE treatment market is substantial and it's growing. The market was greater than $2 billion in 2022 and is expected to grow to over $4 billion by 2028. This predicted growth is based on patients being diagnosed earlier, more patients taking preventative treatments as well as the expansion of available therapies in more geographic regions. We conducted market research with essential stakeholders, both healthcare providers and HAE patients. In the middle of the slide, we show results from a survey we conducted with U.S. physicians where we shared a blinded product profile of a monoclonal antibody inhibitor of plasma kallikrein, with efficacy comparable to market leader TAKHZYRO, but with a dosing regimen of every 3 months. The physicians rated on a 7-point scale, how likely they would be to prescribe a product with this profile and the average rating was a 6.5, indicating a high motivation to prescribe. On the far right-hand side, we see the results of a survey of 101 patients, where we shared the same blinded product profile. All the patients surveyed were willing to try a product in this profile with close to 70% being very willing to either start or switch to a product with this profile. I'll now hand it back to Chris, who will review the clinical results that we've seen up today -- to date . Chris?

Thanks, Andrew. As we've discussed, we are developing therapies that have the potential to be first choice treatments with validated mechanisms and differentiated profiles. 0215 inhibits plasma kallikrein, which is a validated mechanism in HAE, leveraging the same mechanism as market leader TAKHZYRO. Our goal with STAR-0215 is to reduce disease and treatment burden to normalize patients' lives as currently available therapies at high burden of administration or limited efficacy. STAR-0215 profile is also differentiated as the YTE extended half-life supports self-administered dosing once every 3 or 6 months and it has also been formulated without citric acid to reduce painful administration for patients. We have been. We have seen encouraging clinical results to date with a potential best-in-class PK profile, long plasma half-life, and sustained inhibition of plastic kallikrein, which I will review more on the next slide. We shared initial results from our Phase Ia healthy subject clinical trial. These results showed that STAR-0215 was well tolerated with a favorable safety profile. We also saw a rapid and sustained achievement of STAR-0215 concentrations consistent with clinical benefit after single subcutaneous doses. The estimated half-life of STAR-0215 is up to 117 days or 5x longer than lanadelumab. We also saw that STAR-0215 achieved sustained inhibition of plasma kallikrein. Later this year, we are planning to share additional results from this trial that are expected to provide more information on our plans for dosing STAR-0215 every 3 or 6 months. Here, we look at what those 3- and 6-month dose regimens could look like in more detail. This is a pharmacokinetic model, which is based on initial human pharmacokinetic data from the Phase Ia trial of the subjects. The last graph shows a model that simulates a potential Q3 month dosing regimen beginning with a 600-milligram loading dose followed by a 300-milligram maintenance dose every 3 months thereafter. As you can see, the model predicts that 0215 could maintain concentrations above the target threshold associated with clinical benefits, and we believe will prevent HAE attacks. This approach to drug administration is being assessed in Cohort 2 in the ALPHA-STAR trial. The right-hand graph shows a simulated Q6 month dosing regimen, which begins with a 600-milligram loading dose than 600 milligrams every 6 months beginning at day 28. Once again, these results show that STAR-0215 could sustain an exposure above the target threshold of 12 micrograms per ml with both Q3 and Q6-month dosing regimens. This approach to drug administration is being assessed in Cohort 3 of the ALPHA-STAR trial. ALPHA-STAR is a dose-ranging proof-of-concept trial in HAE patients, and it remains on track and it is currently enrolling and dosing patients. The cohorts are enrolling sequentially, and we are currently enrolling cohort 3. We anticipate initial proof-of-concept results on schedule in mid 2024. As shown here, we have 3 cohorts in ALPHA-STAR and a target enrollment of 16 patients. All cohorts began with an 8-week run-in period to assess baseline attack rate. Cohort 1 is a single dose cohort among stream 450 milligrams once and following for clinical effects out through 6 months. Cohort 2 has reviewed to the last slide, it's a multiple dose cohort simulating a potential Q3 month regimen starting with a 600-milligram loading dose and followed by a 300-milligram dose 3 months later. Cohort 3 simulates a potential 6-month dosing regimen and begins with a 600-milligram dose followed by a second 600-milligram dose one month later. For each cohort, efficacy will be assessed at 3 months and 6 months intervals after the last 0215 dose was administered. We recently initiated our long-term open-label trial called ALPHA-SOLAR in the fourth quarter of this year for patients that have completed the ALPHA-STAR trial. Pending positive results from ALPHA-STAR, we expect to quickly initiate a single pivotal Phase III trial for STAR-0215 in the first quarter of 2025. I will now hand it back to Jill.

Thank you, Chris. Here, you can see the cadence of anticipated milestones as well as our future development goals for our combined pipeline with at least 1 clinical milestone each year in the coming years. For STAR-0215, we expect to report HAE patient proof-of-concept results for our ALPHA-STAR trial midyear 2024. If results are positive from this trial, we plan to initiate a single pivotal Phase III trial in Q1 of 2025. We are actively working on the design of our Phase III trial. For STAR-0310, we plan to submit an IND by year-end 2024. In 2025, we expect to have early proof-of-concept results for STAR-0310, which we think will teach us a great deal about the PK and PD of this program as well as give us an early read on safety and tolerability. We expect this to be an important readout. In 2026, we anticipate proof-of-concept results in atopic dermatitis patients for STAR-0310 in the second quarter. Our ultimate goal is to bring first choice therapies to patients with our programs, and we are looking forward to executing on that goal in the years to come. We, as a company, want to become a leader in the allergy and immunology space. A company that makes a meaningful difference for patients. STAR-0215 and STAR-0310 fit our corporate strategy of leveraging established mechanisms and advancing programs that we believe can make a meaningful difference for patients. Importantly, the combined pipeline makes us a stronger company and a regular -- gives us a regular cadence of clinical milestones. With that, I will ask the operator to open the question -- the call for your questions. Thank you.

[Operator Instructions] Okay. Great. The first question comes from Eun Yang from Jefferies.

Can you hear me okay? So question is at 0310. It's a very interesting product for a wide range of indications. But the indications that you are looking at are pretty large. So I want to ask you about your medium- to long-term plan with the product. How you are thinking about developing the product to market, is there something that you would be interested in partnering at some point? And the second question is, given that there are 2 same mechanism of action drugs in late stage of development, how important it is for you to see improved or better efficacy aside from lesser frequent dosing? And the last question is -- it's just more of a housekeeping question. $15 million of from payment, is that going to be booked once in R&D in the fourth quarter? And clinical development milestone seems to be minimum about $20 million, but can you kind of comment on your R&D spending for this year as well as the next year?

Thanks for the question, Eun. I'll have Andrea to address your first question.

Sure. In terms of future commercialization strategy for STAR-0310, right now, it's too early to tell. We intend to commercialize STAR-0215 ourselves, certainly, at least in the U.S., and we can possibly leverage some of those resources for commercializing STAR-0310 either on our own or with a partner, and we'll refine our plans as we learn more about the market.

And I believe your second question was around differentiation from the 2 programs that are more advanced than STAR-0310, the Sanofi and the Amgen and the areas where we think it's important to differentiate. And maybe Chris can speak to the potential for differentiation across the 3 axes we've been talking about.

Yes, great. It's an important question. And as Jill points out, there are 3 axes that we think are important here. Number 1 is establishing competitive efficacy. Number 2 is normalizing the dosing administration burden on patients by decreasing the frequency of giving this drug and 3 is favorably differentiating on safety. So yes, efficacy absolutely is important, and we need to be in the ballpark to be in the game. And we think just based on the data we have on hand, targeting OX40 and having rocatinlimab like [indiscernible] potency in vitro gives us the potential to be in the game on efficacy and potentially just because of best-in-class PK characteristics could further differentiate positively on efficacy. Second, the YTE modification is well established and known to prolonged half-life. And we'd expect to see 2- to 5-fold increases potentially with half-life based on YTE modifications just based on literature that's been publicly produced and we're -- based on our hands, the YTE modification and our experience has the potential to prolong half-life, which would therefore decrease dose frequency. And then finally, I went through a lot of reasons why we think we could differentiate favorably on safety, including T cell preservation through a non-enhanced ADCC mechanism with 0310 and by limiting activity to the OX40 receptor instead of the OX40 ligand. So I think, again, all 3 things need to be in play for us to be competitive.

Great. Thanks, Chris. And then the third question, I'll hand to Noah to talk about the $15 million upfront and also a little bit about R&D spending.

We haven't completed a technical accounting memo for the transactions that were just completed. But my preliminary expectation about that upfront is that it would hit R&D expense in Q4 so more to come on that later. But I think the year instinct there is probably correct. And then if I remember correctly, your other question was about the influence on R&D spending over the next couple of years for the new STAR-0310 program. I guess the way I would characterize that is that through the IND-enabling process next year and then into the Ia study in healthy volunteers in the following year. That expense is going to stay relatively modest. I would characterize the split as about 85-15 between the existing STAR-0215 program and the new STAR-0310 program.

And the next question comes from [indiscernible] .

Congratulations. A few questions from us. Will you provide any updates on the preclinical activity of 0310 over the next year or so? Also, how many other compounds are there in the OX40 portfolio? And kind of following on the first question was -- the preclinical data that you showed us today was without the YTE modification. So when can you see additional data with YTE and just another question on the deal terms is what are the specified circumstances under which there can be a reduction in royalties?

Great. Thank you. And so I will start. So we do intend to share preclinical data for the STAR-0310 program next year at a scientific conference. And our intention would be to share data that supports the target product profile that Chris described for the program. In terms of the OX40 portfolio that we in-licensed from Ichnos it includes STAR-0310. It includes telazorlimab and includes some other preclinical, I'll call them lead stage antibodies. In our assessment and analysis of that portfolio, we believe that STAR-0310 has the most favorable characteristics that we think give it the potential to be a best-in-class OX40 program.

In terms of the royalties question, we'll be disclosing more of the details of this agreement in upcoming SEC filings.

And then I think you had a fourth question, which is around when we will share the data with the STAR-0310 containing the YTE and so we have preliminary data that supports the binding affinity for the OX40 receptor as well as data to support the importance of the YTE in its potential for accepting half-life in that data, we would anticipate sharing at an upcoming scientific conference in 2024.

Question. The next question comes from Hartaj Singh at Opp. Co.

Great. Can you hear me?

Yes.

Great. Congratulations, everyone. Really nice in-license here. Just a couple of quick questions. Most of my questions have actually been answered. On 0310, the -- Chris, you've kind of outlined sort of what you're thinking and Jill the milestones. Can you just talk a little bit about over the next 1.5 years, as you're getting the preclinical data you're preparing for an IND by the end of next year, how are you thinking specifically of your clinical strategy? I mean would it be sort of target patients that are hard to treat maybe smaller Phase IIs and IIIs and then try to get to market that way? Is that possible in this market atopic dermatitis? Would you need larger trials? Or is this all to be determined? And then I have a quick follow-up question on 0215 after this one.

Chris?

Yes. Thanks, Hartaj. It's an important question. And we're learning much more about atopic dermatitis endotypes. And we're learning about what are the potential patient types that would respond to various mechanisms and we'll continue to learn more. And while I think it is possible to focus development on specific endotypes, the beauty of this mechanism is that so far, it doesn't look like we need to. And I think that this opens up the possibility of there being a broad population of people that could respond to OX40 pathway inhibition. Now having said that, we'll certainly take advantage of the advances in clinical science to hone our clinical development strategy to be the most efficient possible. And just as a proof of point, we've already outlined an early development strategy that sets us up for potential success there. The Phase Ia and healthy is relatively agnostic and would set us up for the potential of developing this not just in AD but also in other indications. And then the Phase Ib will be able to start to explore the potential of focused development in future trials.

Yes. Chris, that helps a lot. And then just on 0215, I know it's a 0310 call, but I just had to ask this question. Chris, you mentioned that you'll start one Phase III. Is that the expectation right now that between your early to mid-stage programs, one Phase III and the open-label extension, ALPHA-SOLAR, that you could have enough of a database to file with the FDA, assuming everything is positive.