Operator
Good day. Thank you for standing by. Welcome to Subterna's SEP631 Phase 1 Results Conference 1 Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 11 on your telephone. You will then hear an automated message advising that your hand is raised. Please note that today's conference is being recorded. I will now hand the conference over to your speaker host for today, Alex Strauss of Investillations. Please go ahead.
Thank you, Operator. Good morning, everyone, and welcome to Subterna's conference call to review Phase 1 results for SCP-631, which were presented yesterday at Quad AI, and our initial Phase 2 development strategy for mast cell-driven diseases. You can access the slides for today's call by going to the Investors section of our website at ir.subterna.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. In addition, 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, Subterna 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 Feiner, CEO and co-founder.
Thanks, Alex. We're excited to share the results from our phase one trial of SEP 631 and next steps for the program. I'm joined today by Liz Baud, our president and COO, Jake Him, our chief medical officer, and Gil Laboucherie, our CFO. I'll kick things off with a quick introduction to SEPterna, followed by an introduction to SEP 631. Jay will then review our phase one trial results, highlighting the trial safety and pharmacokinetics data as well as pharmacodynamics data, which utilized it in the Catavan Skin Challenge. And Liz will then follow with the discussion on next steps, including our initial phase two strategy. And finally, we'll open it up to Q&A. As a quick intro to Subterna, 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 the drug from a small molecule drug discovery standpoint, and 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 SEP631, our Oral Small Molecule Negative Allosteric Modulator, or NAM, targeting MRGPX2, which is an emerging target for mast cell-driven diseases. And you'll see it's a great example of a program with a meaningful Phase I readout. The other lead program, SEP479, is a parathyroid hormone receptor agonist in development for hypoparathyroidism. And this program is on track to initiate Phase I within the next few months. And 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. Today, we're excited to share the positive the Phase I trial results for SEP631 that we presented yesterday at Quad AI. We believe the preclinical and clinical data generated to date for 631 support a potential best-in-class MRG tracks II 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 surgery carrier, or CSU, in the second half of this year. Beyond On 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 In parallel, we continue to progress our broad strategic partnership with NOVO that we launched last summer, which is focused on five metabolic targets. Before I hand it over to Jay to review our Phase I results, I'd like to spend a few minutes on MRGPROX2, opportunities in mast cell-driven diseases, as well as the preclinical data supporting SCP-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 MRGPX2 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 then release additional ligands, which further amplify mast cell activation in positive feedback loops. We believe that by targeting MRGPX2, 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, so we believe that an MRG-PREX2-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 pyrrhigo. 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 MRG products to 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 SCP-631 and why we're excited about its potentially differentiated profile. 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. 631 is very potent with subnanomolar binding affinity, and we've demonstrated X2 inhibition in cell-based assays in the single-digit nanomolar to high picomolar range. 631 also has a very unique way of completely turning off MRGPX2, and 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 MRGPX2 with the agonist pocket highlighted in teal, and a transmembrane view with an example agonist, in this case quarterstatin-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 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, 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, MRG for X2 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, and 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 631. We then administer a blue dye to give the blood a blue tint. The next thing we do is a skin challenge with an interdermal injection of an X2 agonist, in this case either cordistatin-14 or a catavan. At the site of the injection, we see extravasation of the blue dye into the skin, essentially giving the mouse a little blue hive. And theoretically, if we're able to completely turn off X2 with an inhibitor such as 631, we would ideally see no skin extravasation, and that's exactly what we see. The figure on the right shows you that SCP-631 is able to completely dampen down the skin extravasation for both a cordistatin and a Cataban injections. So this was great, pretty clinical evidence that 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 SCP-631 to have a potential best-in-class profile for mast cell-driven diseases. It has very high potency, the subnanomolar 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. 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, 631 was well-tolerated in our 28-day GLP toxicology studies in both rats and dogs. And finally, we've developed a convenient tablet formulation for once-daily oral dosing. And with that, I'll turn it over to Jay to review our Phase I results.
Thank you, Jeff. I'm excited to present these results from yesterday's late-breaking poster at Quad AI. Turning to the Phase I study design, we conducted a randomized double-blind placebo-control study that included single ascending dose, multiple ascending dose, and open-label crossover food effect cohorts. We evaluated single ascending doses from 10 to 400 milligrams and multiple doses from 10 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 SCP-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 SCP-631. Let's start with a 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 one-and-a-half-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 one-and-a-half-fold the upper limits of normal, was observed with 631, and 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 631 pharmacokinetics, once daily oral 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, and we used two concentrations of a catadir, which is a selective MR-GPR X2 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 Allergy Scope 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, and 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 a 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 drug-mediated inhibition of MR-GPR-X2 signaling in humans. Let us now review the pharmacodynamics of SCP-631. Treatment with 631 resulted in robust, dose-dependent inhibition of a catabat-induced wheel formation. At 10 milligram once daily, the lowest dose evaluated, we observed complete inhibition of wheels induced by catabat at 10 microgram per ml to saline background levels. At the 100-macrogram per ml Akadaban concentration, inhibition was dose-dependent with complete suppression of wheel formation at 90 to 200-milligram 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 631, and demonstrate clinical proof of mechanism. In conclusion, SCP-631 was well tolerated across all study 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 the Cataban-induced skin real formation across all study doses, with complete inhibition observed at doses as low as 10 milligram once daily with a 10 mic per ml at Cataban challenge. These data demonstrate pharmacodynamic evidence of potent MRGPR-X2 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 2 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, Jay. I'm happy to share our Phase II plans for SEP 631 and our thoughts on the broader opportunity for the program and 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 subnanomolar 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, and importantly, there was no food effect. The insurmountable inhibition we observed for all X2 agonists translated very well in our Catabat Skin Challenge, where we observed full inhibition of skin wheel formation at both the low and high doses of the Catabat. Preclinically, we showed SCP-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 SCP-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 is convenient for patients. As Jeff mentioned at the beginning of the presentation, we believe that there is an opportunity for SCP-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 IIb 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 and 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 angiodyma 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 SCP-631. As I mentioned earlier, our plan is to initiate a Phase 2B chronic spontaneous urticaria study in the second half of this year. We're currently running long-term talk studies in both rats and dogs and expect those to be completed mid-year. Our plan will be to initiate our Phase 2b study following the successful completion of those tox studies. Our Phase 2 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 SCP-631, and as demonstrated by our Phase 1 study, we will dose SCP-631 orally once a day. Our primary endpoint will measure the change from baseline in UAS 7 score at week 12. We will also measure key secondary endpoints including safety and tolerability and additional UAS 7 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 SCP-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 underlying 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. So there could be new indications that emerge where SEP631 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 one results for SEP631 not only demonstrate a differentiated clinical profile, but they also provide clear validation of what our native complex platform is capable of delivering. For each of our programs today, 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 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, and this provides us with the flexibility to advance our lead assets and continue investing in innovation. With SEP 631 entering phase two development, SEP 479 approaching the clinic, and additional candidates progressing behind them, we believe Subterna is entering a catalyst-rich period of execution and growth. And with that, I want to thank everyone for joining us this morning, and we can now open up the line for questions.
Operator
Thank you. Ladies and gentlemen, as a reminder, to ask a question at this time, you will need to press star 11 on your telephone and wait for your name to be announced. To withdraw your question, simply press star 11 again. Please stand by while we compile the Q&A roster. Now, first question coming from the lineup. There are Taylor with Wells Fargo. Yolan is now open.
Hey, good morning, and congrats on the data. Look excellent in terms of the competitiveness of this molecule.
So, just two questions from us. I just wanted to know, or can you remind us what dose of the Akataban represents kind of typical endogenous MRG PRX2 levels in disease patients? And I guess, how do you think that's going to inform your go-forward doses for phase two? Yeah, thanks, Eric. 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 of Catabans and the 100, we think we've got a good chance of actually covering that in the skin. But, you know, only time will tell. As we start to work through our phase two 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. And then just a 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. Yeah, thanks, Derek. I'll turn it to Liz to address that question.
So, thanks, Derek. Yeah, great question. As we've 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. So, but the ones that you called out specifically as it relates to intercysticitis and migraines. 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 within those particular tissues. And so that's what we're really continuing to focus on, understanding those models as well as understanding 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. And so we're aggressively trying to figure out what's really the best strategy. And as we said earlier, we're trying to figure out what's the best approach and cost-effective later before we're here.
Great. Thanks, Liz, and congrats on the data, guys.
Operator
Thank you. Our next question, coming from the line of Martin Oster 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 for me as well. I guess first, Liz and team, as you're thinking about future indications, just want to 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 two indications post the CSU. And then secondly, on the phase two 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 two currently? Thanks.
Okay, thanks Martin. I'll have, I'll turn the first question over to Liz and the second to Jay.
Yeah, so 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 root area.
Yes, thanks. And with regard to the second question about the doses intended to about 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 SEP631 that it displayed favorable safety and potent efficacy so that we could evaluate the range of pharmacology against the clinical outcomes in each and in the diseases okay thanks for the call guys thanks thank you our next question coming from the lineup Catherine Novak with Jones trading Alanis Melvin hi um good morning thanks very much for taking my questions I was just you know curious if you can give any other color on the transaminate 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 get about maybe why we were seeing them both in the drug and placebo group would be helpful.
Thanks, Catherine. Jay can take this. Thank you, Catherine. Yes, we're very pleased with the safety and tolerability profile observed in the study. And, you know, as we mentioned in totality, the adverse event profile of 6-3-1 was comparable to placebo. First, before we talk about the events, it's notable that more than threefold subjects were treated with 6-3-1 than with placebo. And there were only three liver transaminase elevations observed with 6-3-1, 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. And these are generally not dose-related. As you recall, with 631, it was observed in the 10 milligram and the 30 milligram dose samples in the single dose and in the multiple dose was observed in the in the 200 milligram cohort. But again, you know, in totality, these were transient and comparable to background rates of what was, I would say, spontaneous mild transaminase elevations. And the, yeah, generally the timing of the findings were, you know, variable with respect to the, you know, to the administration of drug.
Okay. And then, you know, again, going back to indications outside of CSU, curious your thoughts, specifically your thoughts on migraine based on recent LUMBEC data looking at the MRG PRX2 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. So the migraine is becoming certainly more of an interesting approach, particularly for mast cells and X2. I mean, I think you're probably aware of the role of neuropeptides within migraines and the Lumbac data certainly suggests as it relates to PACAP, another potential role there as well.
And so I think it's, again, further evidence as we think about how we approach these various indications uh again migraine is a very different study than what we would be doing for uh in the dermatological diseases so 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 rahudem salvaraju with hc when right 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, if there is a point to going higher, and if so, to what level you might look to explore the drug. Secondly, I was wondering if you could give us some additional granularity regarding the specific principal route of excretion of SEP631, 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, Ron. With regard to looking at higher doses, We're actually quite confident that that high dose of 200 milligrams once a day is as high as we really should need to go in any indication. At that level, we think receptor occupancy is way over 99%. And as you can see, even at the high dose of a cat event, we were able to completely suppress wheel formation. So we think that's probably about the high end for any indication. but I'll turn it over to Jay to see if he has any additional comments there.
No, I think that's well said, Jeff. As we have shown, is that even with the high concentration of a catavan, we're able to show complete suppression, so there's really little rationale to push doses any higher than that. Jay, do you want to comment on the metabolism route of excretion? We haven't, we're not disclosing much detail about the, you know, about the excretion pathway of SAD-621, but what we can say is that it's mostly metabolized and that the PK profiles as you see in the, you know, in the release results were very well behaved and it was pretty tight.
Yeah, and there weren't any significant metabolites that we think are active either.
Okay, and then just very quickly, is there any evidence of long-term accumulation in any tissues with this compound?
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 is about 24 hours, we'll get at least a two-fold accumulation or so by around day four or five. We haven't specifically looked at concentration in any specific issues, but we do know that obviously we're getting to the skin.
Operator
Our next question coming from Delaina, Kripa Devarakonda with Truist Security. CLN is now open.
Hey, guys. Thank you so much for taking my question, and congratulations on these early data. Look great. So from the chronic preclinical talk studies that you said you expect in the year, I was wondering if that's a gating factor. for FDA discussions with respect to the trial design, the phase-to-be trial design at all, or you're just waiting for those so that you can go ahead and start the phase-to-be trial design. And, you know, just in terms of targeting X2, given negative data from a competitor of yours and also them deprioritizing their program, 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 that in, 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, thanks, Kribben. With regard to 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 two. We anticipate having readouts from that data mid-year. And as we're talking about starting phase two in the second half of the year, we think the timing is going to 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. But 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 it's drug properties are certainly not ideal for efficacy. It's highly protein-bound, and as a result, it has a very low free fraction. And we think that with CSU, getting the highest level of target engagement is going to be really quite critical. So we're not discouraged by the data, and only time will tell how well our compound works which we think has a superior profile.
Yeah just to expand the response that Jeff gave yesterday, so yes the chronic, so 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 and in answer to your question, the chronic tox would be gating for the initiation of the CSU trial.
Great, thank you so much and congrats again.
Operator
Thank you. Our next question coming from the line of Josh Zimmer with Council Fitzgerald, Elon is now open.
Thanks for taking the question. Congrats on the results. First, do you think you would have 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? And then second, as we think about the potential role of MRG PRX2 in various mass cell disorders, is there any understanding as to why certain patients are susceptible? Are these likely normal reactions to abnormal environments, or are there polymorphisms or other factors that are leading to abnormal reactions mediated by MRG-PRX2 to normal environments?
Yeah, thanks, Josh. With regard to 631 and discovery, you know, our Native Complex platform was really quite critical to this program. 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. And the platform really allowed us to optimize 6.3.1, 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. So 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. So we think it's just generally good for patients to have multiple tools in the hands of the allergists and the other providers.
Operator
Thank you. Thank you. Our next question coming from the line of Test Romeo with JP Morgan. Yalan is now open.
Hey, Jeff and team. Thanks so much for taking our questions this morning. So how do you expect the data and evidence so far to translate into your Phase 2B trial and 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 Jay. Yes, actually, you know, the key objective to a Phase IIb is to identify a dose relationship with benefit-risk as a therapeutic. So while you say, you know, while you mentioned aside from dose, it actually is the key. I think one of the attributes of SCP-631 emerging from, you know, the phase one evidence is that there is a potent pharmacology across a range of doses that are generally well-tolerated so that we can, I think 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 for 12 weeks of dosing and and that we would be evaluating an enriched population of moderate to severe CSU with patients who remain symptomatic despite second-generation H1 antihistamines.
And we'll have more detail to say about that phase two trial as it gets going.
Operator
Thank you. And there are no further questions in here at this time. I will now turn the call back over to Mr. Jeff Beiner for any closing comments.
Yeah, once again, I want to thank everybody for joining us today. Again, we're very excited about the data that we've seen, and we're very excited about the future potential of 631 in several mast cell-driven diseases. And thanks again, and we hope to provide further updates in the future.
Operator
Ladies and gentlemen, this concludes today's conference call. Thank you for your participation, and you may now disconnect.
