Please note that today's conference is being recorded. I will now hand the conference over to your speaker host for today, Alex Straus of Investor Relations. Please go ahead. Thank you, operator. Good morning, everyone, welcome to Septerna's Conference Call to review phase I results for SEP-631, which were presented yesterday at AAAAI and our initial phase II development strategy for mast cell-driven diseases. You can access the slides for today's call by going to the investor section of our website at ir.septerna.com. Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those set forth in the risk factor section of our most recent annual report on Form 10-K and any other filings that we may make with SEC. Any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, Septerna specifically disclaims any obligation to update or revise any forward-looking statements, even if our views change. With that, I will turn the call over to Jeff Finer, CEO and co-founder. Thanks, Alex. We're excited to share the results from our phase I trial of SEP-631 and next steps for the program. I'm joined today by Liz Bhatt, our President and COO, Jae Kim, our Chief Medical Officer, and Gil Labrucherie, our CFO. I'll kick things off with a quick introduction to Septerna, followed by an introduction to SEP-631. Jae will then review our phase I trial results, highlighting the trial safety and pharmacokinetic data, as well as pharmacodynamics data, which utilized an icatibant skin challenge. Liz will then follow with a discussion on next steps, including our initial phase II strategy. Finally, we'll open it up to Q&A. As a quick intro to Septerna, since we were founded a few years back, our goal has been to pioneer a new era of GPCR drug discovery, and we've made significant progress towards that goal. We've developed a new way to do drug discovery for GPCRs that we call our Native Complex Platform. This platform has allowed us to discover new chemical matter for several GPCR targets that have been historically challenging to drug from a small molecule drug discovery standpoint. It's also allowed us to rapidly optimize lead compounds using structure-based drug design. This has very quickly yielded a rich portfolio. Our strategy from the outset has been to pursue programs with validated targets, early clinical readouts, and large commercial opportunities. Today, we'll focus on SEP-631, our oral small molecule negative allosteric modulator or NAM, targeting MRGPRX2, which is an emerging target for mast cell-driven diseases. You'll see it's a great example of a program with a meaningful phase I readout. The other lead program, SEP-479, is a parathyroid hormone receptor agonist in development for hyperparathyroidism. This program is on track to initiate phase I within the next few months. Importantly, we're well capitalized with a cash runway to advance our portfolio at least into 2029. Here's an overview of our pipeline today. Our strategy as a company has been to go after important GPCR targets independent of therapeutic area. We're focused initially on GPCR targets in endocrinology, immunology, and inflammation, as well as metabolic diseases, but we have a number of earlier stage programs in other therapeutic areas. We're excited to share the positive phase I trial results for SEP-631 that we presented yesterday at AAAAI. We believe the preclinical and clinical data generated to date for 631 support a potential best-in-class MRGPRX2 profile, including robust pharmacodynamic inhibition, sustained once-daily pharmacokinetics, and a favorable safety profile. Based on that, we anticipate initiating phase II development, initially in chronic spontaneous urticaria or CSU, in the second half of this year. Beyond our two lead assets, we have an earlier stage program targeting the thyroid-stimulating hormone receptor for Graves' disease and additional undisclosed early discovery efforts as well. In parallel, we continue to progress our broad strategic partnership with Novo Nordisk that we launched last summer, which is focused on five metabolic targets. Before I hand it over to Jae to review our phase I results, I'd like to spend a few minutes on MRGPRX2 opportunities in mast cell-driven diseases, as well as the preclinical data supporting SEP-631's potential best-in-class profile. MRGPRX2, which you may hear us refer to as X2 from time to time, is an emerging mast cell target that's activated by dozens of endogenous ligands, including neuropeptides, immune mediators, as shown on this figure, as well as several others. It's important to understand that mast cells are strategically localized near both sensory neurons and also around tissue capillaries so that they can quickly respond to allergens and other stimuli. When MRGPRX2 is activated, this leads to mast cell degranulation through an IgE-independent pathway, causing release of several mast cell mediators that lead to pain and itch through sensory neurons, as well as inflammation and edema through effects on nearby capillaries. Sensory neurons and immune cells can release additional ligands, which further amplify mast cell activation and positive feedback loops. We believe that by targeting MRGPRX2, we have the potential to disrupt these feedback loops to control overactivation, which occurs in several mast cell-driven diseases. Mast cells are known to be involved in a broad range of allergic and inflammatory diseases that affect organ systems throughout the body. We believe that an MRGPRX2-targeted medicine may have broad therapeutic utility across a wide spectrum of indications. Mast cells are particularly prevalent in the skin and thought to be involved in urticaria, which we'll discuss in more detail later, as well as atopic dermatitis and prurigo. Mast cells are also particularly prevalent in mucosal surfaces throughout the body, including in the respiratory tract, where they play a role in asthma and allergy, in the GI tract, where there's emerging evidence for their roles in irritable bowel syndrome and IBD, as well as in the bladder, where there's increasing evidence of their potential role in interstitial cystitis or bladder pain syndrome. Interestingly, there have been recent papers suggesting potential roles of mast cells and MRGPRX2 in mediating pain associated with migraine due to their presence in the meninges, as well as pain associated with gout and rheumatoid arthritis due to their localization in synovial fluid around joints. Given all of these potential roles, we think that an MRGPRX2 therapeutic may represent a large pipeline and a product opportunity. I want to now introduce you to SEP-631 and why we're excited about its potentially differentiated profile. SEP-631 is an oral small molecule that inhibits MRGPRX2 through a negative allosteric modulator or NAM mechanism, meaning that it binds outside of the agonist binding pocket. SEP-631's very potent, with sub-nanomolar binding affinity, and we've demonstrated X2 inhibition in cell-based assays in the single-digit nanomolar to high picomolar range. SEP-631 also has a very unique way of completely turning off MRGPRX2. We want to introduce you to additional details on its mechanism action for the first time today. Here we're looking at a figure that shows both the extracellular view of MRGPRX2 with the agonist pocket highlighted in teal, and a transmembrane view with an example agonist, in this case, Cortistatin-14, in the pocket highlighted in blue. One of the extracellular loops of the receptor is highlighted in magenta just as a reference point. Turning to the figures on the right, when SEP-631 binds to X2, you can see that the agonist binding pocket is essentially completely closed, which prevents binding of all agonists. To further enhance the effect, SEP-631 has a very slow off-rate. Once it's bound to X2, it can be on the receptor without dissociation for hours. The combination of all these features gives 631 what we call an insurmountable negative allosteric modulator or insurmountable NAM profile, meaning that once the receptor is turned off, 631 can't be outcompeted by excess amounts of endogenous ligands. Finally, 631 has excellent pharmaceutical properties, including a preclinical PK profile across species that projected to once-daily dosing in humans, and you'll see in a few minutes that this translated well to QD dosing in our phase I trial. In terms of preclinical animal data, MRGPRX2 presents a challenge in that it's not well conserved across species. We had to make a knock-in mouse by replacing the mouse's gene with the human X2 gene. We've used these mice in a model shown here that we think is particularly relevant for urticaria. We start by treating the mice with an oral dose of SEP-631. We administer a blue dye to give the blood a blue tint. The next thing we do is a skin challenge with an intradermal injection of an X2 agonist, in this case, either Cortistatin-14 or icatibant. At the site of the injection, we see extravasation of the blue dye into the skin, essentially giving the mouse a little blue hive. Theoretically, if we're able to completely turn off X2 with an inhibitor such as SEP-631, we would ideally see no skin extravasation, and that's exactly what we see. The figure on the right shows you that SEP-631 is able to completely dampen down the skin extravasation for both the Cortistatin-14 and icatibant injections. This was great preclinical evidence that SEP-631's insurmountable NAM profile could now translate into an in vivo model. To wrap things up before we share the clinical trial results, we believe that the preclinical data we've generated to date support the potential for SEP-631 to have a potential best-in-class profile for mast cell-driven diseases. It has very high potency with sub-nanomolar binding affinity and a very slow off rate. The insurmountable NAM mechanism completely closes off the agonist binding pocket, as we shared for the first time today. This translated to excellent activity in our knock-in mouse model, as we just discussed. SEP-631 also has outstanding pharmaceutical properties, including oral PK properties across species that support once daily dosing in humans and low risk for drug-drug interactions and food effects. In terms of preclinical safety studies, SEP-631 was well-tolerated in our 28-day GLP toxicology studies in both rats and dogs. Finally, we've developed a convenient tablet formulation for once daily oral dosing. With that, I'll turn it over to Jae to review our phase I results. Thank you, Jeff. I'm excited to present these results from yesterday's late-breaking poster at AAAAI. Turning to the phase I study design, we conducted a randomized double-blind placebo-controlled study that included single ascending dose, multiple ascending dose, and open label crossover food effect cohorts. We evaluated single ascending doses from 10 milligrams to 400 milligrams and multiple doses from 10 milligrams up to 200 milligram once daily for 10 days. In the multiple dose part of the study, we incorporated a skin challenge test to directly assess MRGPRX2 receptor target engagement and pharmacodynamics in humans. Additionally, the effect of food on orally administered SEP-631 was assessed in a crossover design to compare fasted to fed pharmacokinetics. The primary objective of the study was to assess the safety and tolerability of single and multiple doses of oral SEP-631. Let's start with the single dose safety profile. Across single dose cohorts up to 400 milligrams, the rate of treatment emergent adverse events was comparable to placebo. No severe or serious adverse events were reported, and the majority of adverse events were mild. Two transaminase elevations were observed. Both were mild, less than 1.5-fold the upper limits of normal, not dose-related, and occurred at rates comparable to placebo. Overall, the single dose data support a favorable tolerability profile across a broad dose range. Looking next at the multiple dose safety profile. With 10 days of once daily dosing from 10 milligram up to 200 milligrams, adverse event rates were again comparable to placebo, and no severe or serious adverse events were reported. One mild transaminase elevation, less than 1.5-fold the upper limits of normal, was observed with SEP-631. One elevation was observed with placebo. Importantly, no safety signals emerged with repeat dosing. Together, the single and multiple dose safety data support a wide range of doses for future clinical studies. Turning now to SEP-631 pharmacokinetics. Once daily oral SEP-631 for 10 days demonstrated approximately dose proportional exposure across the evaluated dose range. The elimination half-life was approximately 24 hours, supporting convenient once daily dosing. In the food effect crossover part of the study, exposure was similar under fed and fasted conditions, supporting dosing without food restrictions. To evaluate pharmacodynamic activity, a skin challenge test was used to assess target engagement in the multiple dose cohorts at steady state. Intradermal injections, as shown in the upper right panel, were performed with saline as control for injections, histamine as positive control. We used two concentrations of icatibant, which is a selective MRGPRX2 agonist, to induce X2-dependent wheel formation. Skin challenges were performed at pre-dose baseline and at steady state on day nine following drug or placebo treatment. Skin wheels in this study were measured using the AllergyScope detector, a precision skin wheel detection platform that uses shortwave infrared imaging, shown here in the lower right panel. Images were transmitted and centrally analyzed. Measurements were performed by two independent adjudicators blinded to treatment assignment, providing objective analysis with high reproducibility. By way of comparison, the traditional approach to skin testing is that each wheel is measured manually by a technician who outlines the wheel with a hand-drawn ink marker and measured with a ruler to a whole millimeter scale, which is highly subject to operator variability. Using our method, baseline skin challenge data showed highly reproducible wheels formed by icatibant at 10 and 100 microgram per mL, with change from saline dynamic range comparable to historic values with high precision and scale to the decimal point of a millimeter. Our approach enables high precision, independently adjudicated quantification of MRGPRX2 signaling in humans. Let us now review the pharmacodynamics of SEP-631. Treatment with 631 resulted in robust dose-dependent inhibition of icatibant-induced wheel formation. At 10 mg once daily, the lowest dose evaluated, we observed complete inhibition of wheels induced by icatibant at 10 microgram/mL to saline background levels. At the 100 microgram/mL icatibant concentration, inhibition was dose-dependent, with complete suppression of wheel formation at 90 mg-200 mg once daily doses. The data show low variability, as demonstrated by the standard deviation bars, and high degree of nominal statistical significance compared to baseline at all doses evaluated. These findings demonstrate the precision of the pharmacodynamics methodology, complete functional blockade of X2 signaling in humans by SEP-631, and demonstrate clinical proof of mechanism. In conclusion, SEP-631 was well-tolerated across all studied doses. The elimination half-life is approximately 24 hours, and the pharmacokinetic profile supports once daily oral dosing without food restrictions. 631 treatment resulted in robust inhibition of icatibant-induced skin wheel formation across all studied doses, with complete inhibition observed at doses as low as 10 mg once daily with a 10 micro per mL icatibant challenge. These data demonstrate pharmacodynamic evidence of potent MRGPRX2 inhibition by 631 in humans, and supports clear clinical proof of mechanism that 631 engages its cognate receptor target and inhibits downstream signaling, blocking mast cell degranulation. We believe that these results strongly support advancement into phase II development in patients with mast cell-driven diseases, including chronic spontaneous urticaria. I will now turn it over to Liz to talk about our plans in that area. Thanks, Jae. I'm happy to share our phase II plans for SEP-631 and our thoughts on the broader opportunity for the program in several different mast cell-driven diseases. We believe the preclinical and clinical data that we've generated with SEP-631 supports a potential best in class X2 profile based on the following observations. Our in vitro sub-nanomolar binding affinity and slow receptor off-rate kinetics translated to high receptor occupancy in humans. Our excellent preclinical PK was confirmed in healthy volunteers to be a 24-hour half-life, which means we will be able to dose patients once daily. Importantly, there was no food effect. The insurmountable inhibition we observed for all X2 agonists translated very well in our icatibant skin challenge, where we observed full inhibition of skin wheel formation at both the low and high doses of icatibant. Preclinically, we showed SEP-631 was generally well-tolerated in GLP tox studies, and in the clinic, the AEs were considered mild, and there were minimal other observations. In summary, we believe SEP-631 has the potential to have best-in-class profile. We have excellent potency with a mechanism that provides broad insurmountable inhibition. While we are waiting for long-term preclinical tox studies, our early clinical safety profile is clean. We also have a convenient once daily dose with a tablet that can be taken whenever it's convenient for patients. As Jeff mentioned at the beginning of the presentation, we believe that there is an opportunity for SEP-631 to treat a broad array of diseases driven by overactivation of mast cells. Since the skin has the highest level of X2 expression on mast cells, our initial strategy is to rapidly advance into chronic urticaria studies. First, we will be initiating a phase II-B study in chronic spontaneous urticaria in the second half of this year. Second, following initiation of our CSU study, we will pursue an open label chronic inducible urticaria study in symptomatic dermatographism patients. As we've shared before, we are very excited about the breadth of the opportunity for X2 inhibition in mast cell-driven diseases. As such, we're actively exploring the path forward in a select number of other high potential indications, including atopic dermatitis, interstitial cystitis, migraine, as well as asthma. We plan to share more details about potential development plans in these areas in the future. Let's focus on chronic spontaneous urticaria. This is a challenging dermatological disease that is characterized by itchy and painful wheels caused by the mediators that are released from mast cells, as well as angioedema resulting from vascular leakage, also caused by the mediators. Managing CSU is a big challenge for patients. As you can see from this real-world patient study and these photos, CSU has a very high impact and burden on patients' daily lives. Patients are in considerable pain, they have significant anxiety and depression, and often miss work to manage their disease. Patients are initially treated with high doses of antihistamines, but at least 40% of them are refractory, and as a result, there's a very high unmet need for additional treatment options, particularly oral products like SEP-631. As I mentioned earlier, our plan is to initiate a phase II-B chronic spontaneous urticaria study in the second half of this year. We're currently running long-term tox studies in both rats and dogs and expect those to be completed mid-year. Our plan will be to initiate our phase II-B study following the successful completion of those tox studies. Our phase II will be a double-blind placebo-controlled global study. The high level schematic of the study design is shown here. We plan to recruit adult CSU patients that have moderate to severe disease and who remain symptomatic on second-generation antihistamines. We intend to study up to four doses of SEP-631, and as demonstrated by our phase I study, we will dose SEP-631 orally once a day. Our primary endpoint will measure the change from baseline in UAS7 score at week 12. We will also measure key secondary endpoints, including safety and tolerability and additional UAS7 measures. As a reminder, we also intend to pursue an open-label chronic inducible urticaria study following initiation of our CSU study. As I mentioned earlier, we're excited to be able to explore whether SEP-631 has the potential to be used in other mast cell-driven diseases with high unmet medical need. The indications that we have selected are ones where mast cells play a central role in the disease pathology, and there's evidence of X2 being expressed on the tissue-resident mast cells. We have initially prioritized four additional indications: atopic dermatitis, interstitial cystitis, migraine, and asthma for further evaluation. These particular diseases span multiple target organs and represent distinct cardiac pathologies. As a result, clinical outcomes in one setting may not predict performance in another, creating multiple independent development opportunities for SEP-631. Each indication presents a different level of unmet need, and the positioning of an X2 product in the treatment landscape will also vary. As we continue to do deeper diligence, we will prioritize the opportunities that offer the strongest probability of clinical and commercial success and may ultimately choose to advance all or a focused subset of these indications to maximize value creation. Our strategy is to develop cost-efficient, right-sized clinical development plans to be able to demonstrate clinical proof of concept in these diseases. In certain indications, this may take the form of a dose range study. While in others, a single dose design may be sufficient to detect an early efficacy signal. Determining the optimal approach for each indication is part of the deeper evaluation that is currently underway. One exciting thing about the field is that researchers continue to work extensively on diseases driven by mast cells and X2 in particular. There could be new indications that emerge where SEP-631 should be evaluated. We will plan to share more information on our strategy and these additional indications over time. Jeff, I'll hand it back to you to wrap up. Thanks, Liz. To wrap things up, we believe that the positive phase I results for SEP-631 not only demonstrated a differentiated clinical profile, they also provide clear validation of what our Native Complex Platform is capable of delivering. For each of our programs to date, we've used the platform to discover novel binding pockets, find new ways to unlock historically challenging GPCRs, and rapidly optimize high-quality candidates using structure-based drug design. The translation of SEP-631 from discovery through clinical proof of mechanism reinforces the strength and reproducibility of this approach. We're building a robust pipeline that includes multiple wholly owned programs, each of which targets an unmet need and represents a compelling market opportunity. In parallel, we're extending the reach of our platform through strategic partnerships, including our collaboration with Novo focused on five metabolic targets. We remain well-capitalized with cash runway at least into 2029. This provides us with the flexibility to advance our lead assets and continue investing in innovation. With SEP-631 entering phase II development, SEP-479 approaching the clinic, and additional candidates progressing behind them, we believe Septerna is entering a catalyst-rich period of execution and growth. With that, I want to thank everyone for joining us this morning, and we can now open up the line for questions. Thank you. Ladies and gentlemen, as a reminder, to ask a question at this time, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, simply press star one one again. Please stand by while we compile the Q&A roster. Now first question coming from the line of Derek Archila with Wells Fargo. Your line is now open. Hey, good morning and congrats on the data. Look excellent in terms of the competitiveness of this molecule. Just two questions from us. I just wanted to know, or can you remind us what dose of the icatibant represents kind of typical endogenous MRGPRX2 levels in disease patients? I guess, how do you think that's gonna inform your go-forward doses for phase II? Yeah, thanks, Derek Archila. you know, with regard to endogenous levels, you know, it's actually really quite difficult to tell across indications. We think that between the 10 microgram per mil icatibant and the 100, we think we've got a good chance of actually covering that in the skin. you know, as only time will tell as we start to work through our phase II program, the endogenous levels across other indications actually could be quite different. Only time will tell as we demonstrate our clinical efficacy later. Got it. Very helpful. Just second question. You brought up interstitial cystitis and migraine as, you know, potential indications in the past. Maybe you can just expand on the biological rationale for those and I guess where do you kind of see them in the pecking order on, you know, indications post CSU and CIndU. Thanks. Yeah. Thanks, Derek. I'll turn it to Liz to address that question. Thanks, Derek. Yeah, great question. As we said, we're really excited about the breadth of the opportunity here. You know, we are really evaluating all those four that we've indicated right now in parallel. But the ones that you called out specifically as it relates to interstitial cystitis and migraine, there has been recent work in the academic world as it relates to demonstrating the presence of mast cells as well as the presence of X2 with those within those particular tissues. That's what we're really continuing to focus on, understanding those models as well as understanding, you know, the presence of X2 and how we would think about doing clinical development there. Again, those are just, I think, certain examples of the breadth of the opportunity here. New indications are actually being identified regularly, we're aggressively trying to figure out what's the best strategy. As we said earlier, we're trying to figure out what's the best approach and a cost-effective way to move forward here. Great. Thanks, Liz, and congrats on the data, guys. Thanks. Thank you. Our next question coming from the line of Martin Auster with Raymond James. Your line is now open. Hey, guys. Thanks for taking the question. Congratulations on demonstration of an excellent early clinical profile today. I think just a couple from me as well. I guess first, Liz and team, as you're thinking about future indications, just wanna get a sense of sort of what the timeline might be as you're kind of weighing through those and when you think potentially you could look at starting additional phase II indications post the CSU. Secondly, on the phase II CSU trial, I notice you're provisionally thinking about having four doses similar to the four doses you had in the MAD. Obviously, pending the results of the long-term chronic tox, are you thinking about a similar dose range in the phase II currently? Thanks. Okay. Thanks, Martin. I'll turn the first question over to Liz and the second to Jae. Yeah. As it relates to the indications, our number one priority is to rapidly advance into the urticaria indications that we mentioned earlier, initially into CSU and then to chronic inducible urticaria. We can't give a timeline right now as it relates to the other ones. We're continuing those evaluations, but really our number one priority is getting going in the urticarias. Yes. Thanks. With regard to the second question about the doses intended to be evaluated in the phase II CSU trial, our placeholder is approximately three to four doses and in the dose range that was explored in the MAD study. I think an attribute of SEP-631 that it displayed favorable safety and potent efficacy so that we could evaluate the range of pharmacology against the clinical outcomes in the diseases. Okay. Thanks for the color, guys. Thanks. Thank you. Our next question coming from the line of Catherine Novak with JonesTrading. Your line is now open. Hi. Good morning. Thanks very much for taking my questions. I was just, you know, curious if you can give any other color on the transaminase increases. I mean, it, you know, it looks like they're occurring at the same rate in the placebo. I just wanted to maybe get an understanding of, you know, at what point after dosing did they occur? You know, were they transient? Any other, you know, any other indication that you can give about maybe why we're seeing them both in the drug and placebo group would be helpful. Great. Thanks, Catherine. Jae can take this. Yes. Thank you, Catherine. Yes, we're very pleased with the safety and tolerability profile observed in this study. You know, as we mentioned in totality, the adverse event profile of SEP-631 was comparable to placebo. First, before we talk about the events, it's notable that more than t-fold subjects were treated with SEP-631 than with placebo. There were only three liver transaminase elevations observed with SEP-631, and there were two observed with placebo. All of them were transient. Less than one and a half fold below the upper limits of normal. These are generally not dose-related, as you recall, with 631, it was observed in the 10-milligram and the 30-milligram dose levels in the single dose and in the multiple dose, was observed in the 200 milligram cohort. Again, you know, you know, in totality, these were transient and comparable to background rates of what was, I would say spontaneous mild transaminase elevations. Generally the timing of the findings were, you know, variable with respect to the, you know, to the administration of drug. Okay. You know, again, going back to indications outside of CSU, curious your thoughts, specifically your thoughts on migraine, based on recent Lundbeck data looking at the MRGPRX2 pathway in migraine. You know, how has this maybe these learnings influencing your prioritization of additional programs? Yeah, it's a great question and comment, Catherine. The migraine is becoming certainly more of an interesting approach, particularly for from mast cells and MRGPRX2. I mean, I think you're probably aware of the role of neuropeptides within migraines and the one that data certainly suggests as it relates to PACAP, another potential role there as well. I think it's again, further evidence as we think about how do we approach these various indications. Again, migraine is a very different study than what we'll be doing for in any dermatological diseases. We need to spend some time to figure out how we might approach that space. Got it. All right, thanks very much. Thanks. Thank you. Our next question coming from the line of Raghuram Selvaraju with H.C. Wainwright. Your line is now open. Thanks so much for taking my questions and congratulations on this excellent early data. I was wondering if you could give us a sense of to what extent you believe there might be benefits to exploring higher doses than the upper end of the range that were explored in the phase I study, particularly from the standpoint of target engagement, you know, if there is a point to going higher, and if so, to what level, you know, you might look to explore the drug? Secondly, I was wondering if you could give us some additional granularity regarding the specific principle route of excretion of SEP-631 as well as any noteworthy metabolites that have been identified that appear to be biologically active, and if you have any plans to explore those further? Thank you. Yeah, thanks, Raghuram. With regard to looking at higher doses, we're actually quite confident that that high dose of 200 milligrams once a day, it is as high as we really should need to go in any indication. At that level, we think receptor occupancy is way over 99%. As you can see, even at the high dose of icatibant, we were able to completely suppress wheel formation. We think that's probably about the high end for any indication. I'll turn it over to Jae Kim to see if he has any additional comments there. No, I think that's well said, Jeff. You know, as we had shown is that even with the high concentration of icatibant, we were able to show complete suppression. There's really little rationale to push doses any higher than that. Jae, do you wanna comment on the metabolism route of excretion? The, yeah, we're not disclosing much detail, about the, you know, excretion pathway of SEP-631. What we can say is that it's mostly metabolized and that the PK profiles, as you see in the, you know, in the released results were very well behaved and it was pretty tight. Yeah. There weren't any significant metabolites that we think are active either. Okay. Just very quickly, is there any evidence of long-term accumulation in any tissues with this compound? I mean, that's a good question. That's something we haven't looked at in a lot of detail. We do think in terms of accumulation over since the half-life's about 24 hours, we'll get at least a twofold accumulation or so over by around day four or five. We haven't specifically looked at concentration in any specific tissues. We do know that obviously we're getting to the skin. Thank you. Our next question coming from the line of Kripa Devarakonda with Truist Securities. Your line is now open. Hey, guys. Thank you so much for taking my question and congratulations on these early data. Look great. From the chronic preclinical talk studies that you said you expect mid-year, I was wondering if that's a gating factor for FDA discussions with respect to the trial design, the phase II-B trial design at all, or you're just waiting for those so that you can go ahead and start the phase II-B trial design? You know, just in terms of targeting X2, you know, given negative data from a competitor of yours and also them deprioritizing their programs. There continues to be a little bit of skepticism around targeting X2. Obviously, the data that you've shown today look great. Can you help us put these data in the context of that skepticism? Is it the mechanism that you guys have? Is it, you know, does this validate that as a target? Thank you. Yeah. Yeah. Thanks, Kripa. With regard to that, your first question about, you know, preclinical, the long-term tox study. We decided to start that study well in advance so that we actually had that study completed before the phase II. We anticipate having readouts from that data mid-year. As we're talking about starting phase II in the second half of the year, we think the timing's gonna work out just well for that. You know, with regard to the other program that you mentioned, where there was a program that was deprioritized. Part of that was for preclinical safety reasons, and that relates to your first question as to why we decided to start the chronic tox studies early. In terms of their data, we think it's actually got limited, their data in CSU. We think it's got limited read-through. We've done some follow-up research on the properties of that drug, and its drug properties are certainly not ideal for efficacy. It's highly protein bound. As a result, it has a very low free fraction. We think that with CSU, getting the highest level of target engagement is gonna be really quite critical. We don't, we're not discouraged by the data. Only time will tell how well our compound works, which we think has a superior profile. That's great. Thank you so much. Jae? Yeah. Jae. Just to, yes, to expand the response that Jeff gave. Yes, the chronic. We decided to go from the initial study enabling short-term tox directly to chronic tox in support of the phase II campaign. A CSU phase II trial is expected to be a possibly 12 weeks of treatment. In answer to your question, the chronic tox is would be gating for the initiation of the CSU trial. Great. Thank you so much, and congrats again. Thanks. Thank you. Our next question coming from the line of Josh Schimmer with Cantor Fitzgerald. Your line is now open. Great. Thanks for taking the question, and congrats on the results. First, do you think you would've been able to identify the 631 molecule without the Native Complex Platform? What do you see as the implications of these results for the platform in general? Second, as we think about the potential role of MRGPRX2 in various mast cell disorders, is there any understanding as to why certain patients are susceptible? Are these likely normal reactions to abnormal environments? Are there polymorphisms or other factors that are leading to abnormal reactions mediated by MRGPRX2 to normal environments? Thank you. Yeah. Thanks, Josh. With regard to SEP-631 and discovery, you know, our Native Complex Platform was really quite critical to this program. You know, one, you know, as we showed you really for the first time today, the mechanism, that we were able to find a drug that completely turned off the receptor. We would not have known that without the structure-based design approaches that we have. The platform really allowed us to optimize SEP-631, all the parameters in parallel, potency as well as pharmaceutical properties that you've seen translate here today. In terms of your second question about understanding why some patients, there's a lot of heterogeneity in terms of patient responses. This is something that I don't think anybody fully understands at this point in time. As we know in CSU, there's a large number of patients that are refractory to antihistamines, even an additional group of them that are refractory to anti-IgE therapies. It probably is a fairly heterogeneous population, and that's one of the reasons we're excited about the fact that there are several mechanisms that are in development. There's significant unmet need, and it could be that some patients respond to one mechanism and not the other. We think it's just generally good for patients to have multiple tools in the hands of the allergists and the other providers. Great. Thanks very much. Thank you. Thank you. Our next question coming from the line of Tess Romero with J.P. Morgan. Your line is now open. Hey, Jeff and team. Thanks so much for taking our questions this morning. How do you expect the data and evidence so far to translate into your phase II-B trial in patients that you laid out this morning? What are the key design elements that could de-risk this study, and any other aspects you are still working through other than dose? Thank you. Yeah. Thanks, Tess. I'll turn this over to Jae. Yes. actually, you know, the key objective to a phase II-B is to identify a dose relationship with benefit risk of the therapeutic. While I'm, you know, while you mentioned aside from dose, it actually is the key. I think one of the attributes of SEP-631 emerging from, you know, the phase I evidence is that there is a potent pharmacology across a range of doses that are generally well-tolerated so that we can We're well-positioned to evaluate a benefit risk associated with dose and any indication that we're exploring. The other aspects are for CSU design, yes, we have disclosed that our initial plan right now is to evaluate a range of once-a-day doses, you know, against placebo and, you know, with CSU trial convention approximately with 12 weeks of dosing. That we would be evaluating an enriched population of moderate to severe CSU with patients who remain symptomatic despite second generation H1 antihistamines. Yeah. We'll have more details to say about that phase II trial as it gets going. Thank you. Thank you. There are no further questions in the queue at this time. I will now turn the call back over to Mr. Jeffrey Finer for any closing comments. Yeah. Once again, I wanna thank everybody for joining us today. We're again very excited about the data that we've seen, we're very excited about the future potential of SEP-631 in several mast cell-driven diseases. Thanks again, and we hope to provide further updates in the future. Ladies and gentlemen, this concludes today's conference call. Thank you for your participation, and you may now disconnect.