We've got a good schedule. Yeah, thank you. We're good. All right. Good morning, everyone. Welcome to our inaugural Healthcare Innovation Conference. My name is Yatin Suneja. I'm one of the biotech analysts here at Guggenheim. It is my pleasure to welcome our next presenting company, Q32. From the company, we have a few executives here. We have on my left Jodie Morrison, who's the Chief Executive Officer. We also have Shelia Violette. She's the founder and CSO. We have Lee Kalowski, who's the Chief Financial Officer. And then we have Jason Campagna, who's the Chief Medical Officer. Jodie, why don't you make some opening comments? Obviously, there are two big readouts coming up in 4Q, and then you have more stuff coming in the first half of next year. So why don't you just put in perspective the two assets, the upcoming catalyst, and then we'll go into sort of the Q&A. Yeah, absolutely. So the company has sort of two sides to it. We have the initial founding concept, which is around complement therapeutics and tissue targeting, the approach there. We have readouts over next year related to our lead compound there, 097. We have additional assets behind that at DC, as well as some research candidates as well. So that opportunity kind of will come to fruition next year. This year, all eyes are on bempikibart, which is our in-licensed asset originally from BMS that has been moved through two phase 2a programs in atopic dermatitis and alopecia areata. Those readouts are coming now. We've refined that to December. So we're excited to get those readouts out there. We're in the final stages of preparations for that now. So it's an exciting time for the company, collectively focused, obviously, on innate and adaptive immunity. That's really the focus of the organization overall. Got it. Very good. So given that these data are coming first, so let's focus on bempikibart first. Like, what is the mechanism? Why are we seeing sort of this renaissance or like the development of this pathway? Because it's not just you. There are other companies that are sort of pursuing this pathway. Like, what is unique and meaningful about this pathway? Yeah, why don't I hand it to Shelia for that one to start us off? Yeah, so I'll review it. Many of you may already know this, but bemp binds the IL-7 receptor alpha subunit. And as such, it's really a bifunctional antibody because it binds to a region of IL-7 receptor alpha that is shared for binding by both TSLP as well as IL-7. So it's a really unique opportunity to inhibit both TH2 signaling that's mediated by TSLP, although I would say that there's an important region that IL-7, I think, has also into TH2 modulation. And then IL-7 has this really distinct ability to modulate TH1 responses. So with one antibody, a single antibody, it's really a bifunctional antibody that allows you to really broadly remodulate both innate as well as adaptive immunity. Got it. So tezepelumab, which is a TSLP, didn't really work in some of these TH2 diseases, specifically atopic dermatitis. Do you have a hypothesis why? What was the issue with that and how IL-7 receptor alpha sort of addresses that? Yeah. Jason, why don't you start on the clinical trial design for Teze specifically, and then we can talk more sort of on the scientific end? Yeah, I mean, the one good trial that we have in the public domain was the tezepelumab phase 2a, which actually they were thoughtful enough to publish in its entirety. So you can sort of make some sense of it. I think it was in that era, it was a perfectly acceptable and thoughtful trial design. It's not what's done today. And the challenge that they face, like everyone faces, how do you manage topical corticosteroids? These are patients that come in often on lots of topical corticosteroids. Ultimately, to get approved, the drug needs to be shown to be efficacious in their presence, but then it's what you do in the middle. And what Amgen chose to do in that era was allow patients to come into that trial on topical corticosteroids and then optimize the dose of those steroids prior to randomization. So what you had was sort of an optimally treated group of patients on TCS, and then they gave tezepelumab sort of on top of that, and then they were looking for a differential. They did not make their primary endpoint, but I think directionally, the one place that they did find statistical significance was in the itch response, which is, if anything, what would have been predicted from that TSLP mechanism. I think we have a small uncontrolled trial that was released earlier this year with some really high-level data on responses with TSLP. I think that's interesting, but in the absence of placebo, you don't really know. So from our perspective, what we really like about the mechanism of our drug, it's not that it's a TSLP antagonist, although that it is. It's really about the T cell. From our perspective, that IL-7 modulation of the T cell, which allows, as Shelia just noted, not only sort of indirect reach back into that TH2 pathway, but in the case of getting TSLP, we absolutely believe that's required. We're just not convinced that it's both necessary and sufficient to get TSLP alone. You almost certainly need something else with TSLP, given where it sits in the pathway, which is why we like our mechanism a lot. Okay. So the two studies that you are running, or you prioritize two indications, right? Alopecia areata and atopic dermatitis. What led to that prioritization? Is there a biological rationale stronger in one versus the other? Yeah, I think they're different, is what I would say. And I'll let the team get into this, but I think it's worth noting that at the time we selected the two indications, we were in a partnership with Horizon. That was part of the Amgen acquisition and then the ability for us to get that back as a result of some of the overlap there with Amgen's portfolio, including TSLP and others. They're OX40. And so I think ultimately we were able to get the asset back. We looked at it through the marketing lens, I think, through the Horizon side of things and their experience in some of these indications. But they were also two indications that were high on our list, and that allowed us to really think about both the combination of TSLP and IL-7, as well as IL-7 in isolation. So maybe you want to take it from there and kind of talk to the rationale of the scientific piece. Yeah, so when we brought in the asset, we knew that the opportunity was pretty broad for us. We think fundamentally about IL-7 for its ability to really regulate T cell responses. And if you just look at IL-7 cytokine biology, very wide range of diseases. Alopecia was certainly very high on the list, but there are several others. Ulcerative colitis, there's now celiac. There's many different diseases. But we also knew that the antibody did have this ability to block TSLP signaling. And so we thought, well, we should maybe think about widening the net as we think about the disease indications there. And also that fundamental understanding that IL-7 does have this unique ability to have a reach through to amplify TH2 responses. So we thought that this was a good way to think about a couple of shots on goal, hitting overlapping, but somewhat different biology and different disease indications, but where we could execute on a proof of concept trial. Very good. What are, maybe just final question on these mechanisms and high-level stuff, what are some of the safety considerations of this pathway? I mean, we have seen, if I look at the competitors, some sort of reduction in lymphocyte counts. Is that the only thing and how relevant it is to your molecule or maybe how differentiated your molecule is on the safety side? Yeah, maybe, Jason, do you want to take the lead there? So I think it's generally pretty light, for lack of a better concept, but it's a remarkably benign MOA. So we have human data in the literature, and we have a lot of preclinical data. OSE has been thoughtful enough to both publish their preclinical data, remarkably benign. We have Pfizer and GSK human data that were put out early on, although the GSK pharmacology was unusual. They had a lot of ADA. From a safety perspective, both of their drugs were very benign. And in the case of OSE, they're up at 10 mg/kg. Pfizer's workable dose range, when they owned the asset before Xencor, was more like six mg/kg. We're closer to one to three mg/kg. So all of that lines up really well. I think preclinically, our drug, we'll speak to what we know, we went up to 150 mg/kg in non-human primates and didn't hit any dose-limiting toxicities. Even our lymphocyte reductions there, our maximal deflections were about 50% across the board, which was very different than what Pfizer had shown clinically, where they were approaching about 70% reductions at their higher dose. Even then, not much of a safety concern, although I'm noting that lymphocytes may or may not be an issue later in development. Certainly at this stage, there's no evidence on the table that we're looking at anything, I think, really genuinely concerning. Got it. Dipped that to around 50%? We've not gone in our preclinical data, as I said, at 50%, but those are very high doses, like 50 mg/kg and higher. Our human data show us somewhere around 25-ish, 30%. That's where I think it's likely to land when we get our data out. So a very benign safety profile with not a lot of adverse events of special interest, which makes the mechanism very appealing. And we'll see what development brings us. It's early days, but we certainly like what we're seeing to date. Very good. So let's go into the two studies that you're running, AD and AA. If you could talk about the type of patient that you have enrolled in the AD study, the spectrum, how you have managed placebo, not placebo, steroid there, and what your expectations are, basically? Yeah, let me keep going. Sure. So it's the sweet spot population. This is the population in the modern era that has the most unmet need. These are the moderate to severe patients as defined by a combination of EASI, BSA, and IGA. They are, in our trial, it is a monotherapy trial, which is completely standard today. So if you follow, for example, the Sanofi's OX40 ligand program, also monotherapy early in development, it's now while they're in phase three that they will allow both monotherapy and topical corticosteroid allowed treatment. Beyond that, the trial is very similar, I would say, to what the vast majority of sponsors do. There's not a lot of creativity, I think, in AD because you don't need it. But beyond that, it's a straightforward trial. I will note that we allow, I saw this on the list, prior biologic exposures in our trial. Others do as well, but it's unusual, and we're not exactly sure why that dynamic is. It's just unusual to get prior biologic exposures in these trials, even though we know from both now published literature and just talking with KOLs and conference meetings that dupilumab does. Its efficacy has got a lot to be desired for a number of patients, so it seems like a lot of those patients would be going into the clinical trials. We're just not seeing it. Yeah, yeah. How is the baseline? I think in the past, you have characterized that the baseline EASI is closer to, I don't know, 20, low 20s. What does that patient population look like? Yeah, I think the modern clinical trial area, and Lee, please come in here at any time, is generally around that kind of mid to low EASI baseline. Even back in the day, we will note, if you go back to the original dupilumab studies, they were published as a group in the New England Journal of Medicine a number of years ago, but there were three or four of them. Even their EASI scores range, baseline scores were sometimes in the low 20s, sometimes in the high 20s, low 30s. I think it's sort of hit and miss even in that era. But in the modern era. Yeah, I think we'll be consistent. So we've said low to mid 20s would be our expectation for the baseline EASI score. Okay. I think we have discussed in the past about this TH1 versus TH2 phenotype. Can you just talk about that? Do we know when the disease switched to a TH1 or a TH2 phenotype? Is it driven by severity? I think you have better thoughts than I articulated, so. We can talk about what's in the published literature. I mean, this is certainly an emerging area of focus for a lot of the KOLs and a lot of the researchers here, but Jason, do you want to talk about what we know so far? Sure. I think keeping it simple, that sort of ChatGPT summary that you can pull up on Google is, I think, generally accepted now, which just shows how far the field has moved in just five years. But generally speaking, everyone believes that very early on, initial barrier dysfunction and loss of barrier integrity is a TH2-driven event, period, full stop. That TH2-driven event activates a sort of downstream cascade or ensemble of cytokines, which are very early on, again, exclusively TH2, but very quickly you begin to move and toggle up other immunophenotypes, TH1, 17, 22. And generally speaking, that's an age-dependent issue. Children are more TH2 than adult. And it's a time-dependent, acute versus chronic. Acute disease by definition, early, early on is almost all TH2. But once those T cells have had an opportunity to be activated, set up shop in the skin, that's a much more THX, where X can be one, 17, 22. And that seems to be both, Shelia, help me here. It seems to be both what we're seeing with the biomarker ensembles, the RNA, everything's sort of pointing in that direction. Is that right? Yeah, I think it's a combination of histology, looking at various cell types, but a lot of the transcript profiling data. Okay. Very good. Then in terms of the expectation, I mean, I know the endpoint is percentage change, but I think everybody looks at EASI-75 these days or IGA 0/1. So I'm just curious to understand what is the bar here? What would you like to show when the data sort of get presented? Who wants to take the lead there? We like the amlitelimab program a lot. We think it's one; they have the credibility of who they are. Sanofi knows the space. Dupixent's obviously a very good drug. They seem to have set the bar and the kind of future on the field of the data that are coming out of that phase 2 program. We think it's fair. Change from baseline of EASI score around 30% would be a clear win, I think, full stop. EASI-75 and EASI-90 get a little bit more nuanced. It's one of the reasons Sanofi has been particular, I think, about what they put out. On the one hand, we know what those metrics are. The EASI75 scores can be relatively high, upwards of about 40% or higher in early development. But the caveat is that unless you're starting from the same spot, meaning have you a load or not a load, is your dose optimized or not, and when exactly you assessed, week 12, 14, or 16, it matters, so in phase 3, where EASI-75 is part of the co-primary endpoint, everybody starts at the same spot. It's a 16-week trial. All those drugs have loads. All of them have been dose optimized. In 2B, you can look at those EASI-75s and make a very clear argument. Phase 2B depends. It depends. Not everybody had a load. Not everybody had optimal dose. So I think it's a little bit more unclear. That being said, we will report what we find, and I think we like the amlitelimab program. Certainly from a perspective of a data point in a contemporary trial with similar MOA, that's what we would point to. And as you said, our primary endpoints, the mean change, they were right around that 30%. If you look at the placebo-adjusted EASI-75, they were in their 2A a bit north of 30, and then in the 2B a bit south of it. So somewhere in that range, right around 30, one side or the other on the EASI-75 placebo-adjusted, I think would still be relevant. Got it. Are you dose optimized? And And are you loading in phase two in your study? Yeah, maybe I'll start, and then I'll kick it to you. So at this point, we are not dose optimized. We did a run into the phase 2a study that we ran where we looked at two doses that were 2 mg/kg and 3 mg/kg. And we landed at a flat dose of 200, which is roughly in the middle of that. We didn't see much of a differential in what we ran, still blinded as far as data in that aspect. But looking from a pharmacological standpoint, we were comfortable with where we landed. That being said, we now have optimized the formulation such that we could actually go to 300 mg/kg, excuse me, 300 flat dose for patients if we wanted to do a single dose. So we have the ability to dose up, which could actually extend the half-life. We're not sure if it will drive more efficacy, but it certainly would drive the half-life longer. So that's one benefit that we have. But we also have the remission data that we need to look at. So we'll both look at those things in combination. And we did not load in this study. So that's something that we can contemplate for the 2B study that we'll follow as well. Jason, anything to add to that? Only one thing. In the absence of a loading dose, it just should be taken with a grain of salt when you begin to see an effect. We'll have a data point. We'll see an effect. Clearly, with the loading dose, you're almost certainly to see that effect earlier. Back to that question of proportion of patients it hit, we'll say 75 or 90 EASI score. We're assessing a primary endpoint at week 14. That's fine. Other programs have done it. Some do week 12. Some do week 16. But just keep in mind the interplay between a loading dose not yet optimized when we assess the primary endpoint and what those threshold cuts are. Yeah, so just the onset, right? But I think by 14 weeks, you should not have that difference or the loading dose. It's hard to say. I think we like our pharmacology a lot, but until we see the data, it's not exactly clear what a load would or would not bring, which is why we didn't do it. We wanted to understand what the drug looks like in the absence of a load. So we'll let the data tell that story. But loading doses generally clearly will accelerate any effect that you see earlier. Got it. So you had a Part A also, which were inpatient. Are you able to sort of describe the effects that you were seeing there in Part A and any read-through from Part A to B, which is going to readout both going to readout together? Yeah, to be clear, it's still blinded from an efficacy standpoint. So no readouts on any of the critical efficacy endpoints that we're talking about here. There were some findings that were helpful from a pharmacological standpoint. So maybe Shelia or Jason, do you want to tag team that? Sure. So it was a 2 mg per kg and a 3 mg per kg arm. And we used that data to model what were the dose that we wanted to go in at where 90% of the patients would be above the 5 microgram per ml threshold. And the reason why we chose that threshold is that we have full receptor occupancy of T cells at 0.75 microgram per ml in the circulation. But if we wanted to take a more conservative view and assume only 15% of the drug would get into the tissue, we wanted to be sure that we would have full receptor occupancy of those cells in the tissue environment. And thus, that was the back calculation to 5 microgram per ml. Anything else? The only thing I'll add is that what was critical for us is that there were no real differences. It's a small study with a little run-in, but there were no differences in the safety tolerability profile at either 2 or 3 mg/kg. And importantly, lymphocyte reductions appear to be. They overlapped with one another. So it gave us a lot of flexibility to think about that weight-based dosing. And back to what Jodie just said a minute ago, with an optimized now phase 2/3 trial material, the ability to go to 300 milligrams in a single 2 mL injection. We'll see what the larger data set showed, but that Part A would have suggested even back then that we could have gone to the 300 milligram flat dose had we had the formulation for it. Got it. Got it. And then what sort of commercial positioning you are thinking about for if the data are good and you get it approved? I think it'll ultimately depend on the data. I think we need to get to the data before we can make clear proclamations about where we might fit into the treatment landscape. But I think there's certainly a lot of excitement about the approach that's being taken here. And the ability to have both TH2 and TH1 in play at the same time, I think, could be really unique. And so I think we'll wait and see what the data tells us, but we think there's a great opportunity here. And with the market, the size that it is, we can see a lot of different avenues to move forward to be quite a substantial upside for everyone. Got it. So then moving on to AA, smaller study, but very low placebo response in general. What is the bar here? Should we even think about or consider JAK when we are doing a comparison? Yeah, maybe start with a little bit on the design of the trial and then. Yeah, so the trial design, so the only sort of metrics on the wall are the JAK inhibitors, but the trial design is very straightforward. It's a severe and very severe population defined by SALT score. 50-95 makes you severe. Very severe is 95-100. It's a 24-week treatment period, which is the minimum buy-in. I'll turn this over to Lee here sort of to get an efficacy endpoint. And in terms of prior drugs being allowed, they're monotherapy trials. And in terms of prior drugs, there's really nothing approved but JAK inhibitors. And generally, because if patients go off of JAK, they'll lose their hair. It's not something they can just go around and sort of shop in clinical trials. We don't have any expectation. But Lee, you have a trial. Yeah, nothing to really add. I mean, JAKs are, you asked that because that's really it to compare to. But as I'm sure you know, all the dermatologists are desperate or saying we want something other than a JAK showing efficacy with a better safety profile. Yeah. What should be the endpoint that we should be focusing on? We hosted a panel yesterday on the derm side. I think the physicians do care about SALT below 20. That sort of is. But I'm just curious from you to understand. What would you like to show on that particular score? Will you disclose that data or not? Yeah, we certainly expect we're going to disclose that data. We had a recent KOL lunch with Brett King, who's well known in this space, who gave, I think, great perspective on his expectations, which is important to us to understand what the KOLs are looking for. He was putting a mark on the wall of about a 10% in a trial of this context. Important to remember, this is a short trial at 24 weeks, so that there's only really one other comparator you can look at there. The 24 weeks, the loading dose here will be critical in the future for the ramp because it takes a long time to grow hair. That 10% mark for the SALT 20 will be a key point we'll be looking for. And then we'll be looking at other trends within the rest of the data set from there. Okay. Will you announce both the data together, or how are you thinking about the presentation? Yeah, we are expecting to do them at the same time. At the same time. Okay. Anything else about the patient population that you enroll, particularly on AA side, that we should be? Again, it's very typical, at least for the JAK inhibitor program. These are severe, very severe patients. Roughly about a third will be very severe, which is similar to what both baricitinib and ritlecitinib did. It's an open question of what will happen in the future with more moderate patients. On the one hand, everybody agrees that if you have a biologic with biologic-like safety profile, that's a population that's wide open to development. On the other hand, it's more complicated. They have a higher placebo response rate at a minimum, and second, what exactly is the endpoint? SALT 20 is generally accepted by both docs and the FDA, of course, as a meaningful endpoint. They've been less accepting of that endpoint when it comes to the more moderate population. But if the safety profile holds up, I think that's something we're interested in the future. We would obviously explore that with FDA. Got it. Okay. Then maybe moving on to the complement side on 097, if you can just sort of put in perspective the target, the asset, the study that you're running, and what we will learn this year and next year. Yeah, maybe Shelia, do you want to take the lead? You founded the company around this concept, so I feel like it's a good one for you. It's an antibody-derived fusion protein. And basically, the targeting component of it is an antibody that binds to C3d. C3d gets deposited at very high density at sites where complement activation is occurring. And off the tail end of the heavy chain are fragments of the Factor H protein, an incredibly potent regulator of the alternative pathway. So this is differentiated because it's tissue-targeted. We can get full inhibition of complement in disease tissues at doses where we're not inhibiting complement in the circulating compartment. And the mechanism is by inactivation of the convertases, which are critically important as the engines of the complement system. So preclinical studies indicate very good efficacy, low mg/kg dosing once weekly, potentially maybe wider dosing intervals. And so the lead clinical trial for us is a renal basket and alternative pathway complement-mediated diseases. Okay. And then are you going to share anything this year or it's coming first half of next year? Yeah, ultimately, we need to clear out bempikibart data in December now that that's been clarified. So we want to get through that. And then the first half of next year, we'll give a first glimpse at the data from the basket trial and then move to full data by year-end. Are there particular indications within this basket that have enrolled? Are you going to show that data first, or it's going to be all, I think, three indications, right? It's three different indications. And it stands to be determined which ones we might present depending on how many patients come into the early part of the study. Well, very good. I think that's all I had. Rapid fire. Indeed. Thank you so much.