Everyone, we're back again here with the Q32 Bio team. I'm gonna kick it over to CEO Jodie Morrison to do a brief introduction, introduce the rest of the team, and then we'll get into a Q&A. Thanks for joining us, and Jodie, over to you. Great! Thanks so much for the, for the time today, and it's great to be here. Glad to be joined with my team, Lee, Sheila, and Jason, all of which will be presenting today as part of this. Happy to introduce the company if you'd like, Alex, at this time, yeah? Yeah. A quick overview, and then we'll jump into it. Wonderful. So the origin of the company really comes down to the complement side of the house, so originally structured, and the name of the company is, is focused on that, given that Q32 relates to the genes that encode the regulatory complement components. So it's on band q32 of chromosome one. So that really speaks to the origin of the company around the complement side of the house. We've made great progress there in the last seven years and now have a clinical stage asset entering phase II in a renal basket for IgAN, C3G, and lupus nephritis, as well as entering here pretty soon another phase II in ANCA-associated vasculitis, and then we have more assets behind that at the research candidate and DC stage as well. So along the way, we had the opportunity to add to our pipeline of targeted therapeutics with the acquisition of bempi from BMS. Bempi provides a bifunctional approach to IL-7, TSLP, opens the door for Th2 and Th1 disease. We've focused our efforts right now on two phase II programs for atopic derm and alopecia, but lots of opportunity beyond that in diseases that are Th1 and Th2-dominant, and we're excited to really move forward, so we're funded for the phase IIs that we're running, all four of them, into mid twenty twenty-six and are excited about the phase II readouts in the fourth quarter of this year for bempi. Great. Let's jump right into it with bempi. I like the nickname. So with the specific MOA of targeting IL-7 receptor alpha, what do you get beyond just targeting TSLP as it relates to more broadly inhibiting inflammation? Yeah, so I'll— Maybe I'll just— Sheila, take this one. Yeah. Yeah, thanks. So thanks for the question, 'cause I think it's really important for folks is to think about the mechanism of action in bempi and why we think that it will have such broad impact, not only in our lead indications, but in a pretty wide list of inflammatory and autoimmune diseases. So just to take a bit of a step back, bempi is what, you know, we refer to as a bifunctional antibody. It binds to a region on the IL-7 receptor alpha subunit that's shared for binding by both TSLP as well as IL-7 and effectively blocks the signaling of both of these cytokines. I do wanna just mention about TSLP because of the fact that TSLP in and of itself has pretty broad regulatory activity when we think about its ability to modulate immune responses. We think about it a lot for its ability to modulate Th2 differentiation and the production of those cytokines. But I think one of the things that often doesn't get stated is that TSLP can really broadly affect a pretty broad range of other cell types: eosinophils, basophils, mast cells, and innate, lymphoid, cells of the type 2 group. All of those will secrete cytokines that will drive that inflammatory reaction, especially when you have an allergic response, and TSLP also has direct effects on sensory neurons. I then wanna switch to IL-7 because I think classically, we all think about IL-7 as an important regulator of the generation of pathogenic autoreactive T cells and their maintenance, and that's true. But if you look at the literature, it's really rich in a lot of data that really has been generated many years ago that show that IL-7 can actually directly lead to activation of Th2 responses, and I'll talk a little bit about that, but amplify the effects of IL-4. So we know that IL-7 can increase the production of IL-4, a validated target in many ways. It can increase the production of IL-4 from activated T cells, particularly CD4 positive cells. It can do the same on the innate lymphoid cells that I mentioned before, the type two. And IL-7 transgenics, you can see that if you overexpress this in the epithelium, you can get the infiltration of T cells that will actually produce Th2 cytokines, and the IgE levels in the serum of these animals increase. There's lots of other data around fungal infections that do induce an allergic response. You get elevated IL-7 and IL-7 receptors on eosinophils. So I think this is an important point, that we think with this bifunctional antibody, that there's an opportunity to, not only directly through TSLP, impact Th2 responses, but there may well be an important reach-through with IL-7, and particularly in combination with TSLP blockade, really, really have an important reach-through that we often don't talk about. Yep, before we talk about indication selection and trial design, et cetera, can you talk a little bit more about, like, specific biochemical properties of bempi and how it compares to other IL-7 receptor alpha antibody programs out there? Yeah. So we did, you know, a pretty careful analysis of this in a number of different biochemical type of assays, but I wanna emphasize that one of the things as a pharmacologist I think is really important is, what do we understand about the in vivo PK and PD properties? Yep. So if we just think about biochemically, this is a fully human antibody that was generated in the Medarex mice, binds with very, very high affinity to the IL-7 receptor alpha subunit, so it's binding in around 90 picomolar. So that's about 300- to 600-fold higher or better binding affinity than the native ligands. That's critical. We know that based on in vitro biochemical assays, that at the 200 mg flat dose, we're at least 10-fold higher than the IC50 of the TSLP signaling assay and 100-fold higher than the IL-7 signaling assay. What's also important is that this is an IgG1 Fc that's been mutated to basically eliminate effector function and complement activation. So we think that that's an important feature of this molecule. Really, really importantly, the PK of this drug by subcutaneous administration is very good. That subcutaneous administration in the low mg per kg range can get us to the exposure levels where we feel we confidently are attaining full blockade of the receptor pathways. This is data that we generated in our phase I study and then linked to our in vitro data. Great. Y ou know, I wanted to then talk about indication selection, you know, atopic derm and alopecia. I guess specifically starting with atopic derm, you know, how should we, like, think about the failure of tezepelumab in atopic derm and how, you know, how confident are you in atopic derm as an indication? So maybe I can start and then hand it to you, Jason. I think I would say, you know, we're certainly confident that this is a great opportunity for us for a Th1/Th2 disease, where both are present, right? And that sort of atopic march increasingly has supported that, that transition from Th1 to Th2. So we think it's a huge opportunity to really hit both at the same time. As to tezepelumab, I'll hand it off to Jason. Yeah, I think, Alex, it's a good question. It comes up all the time, and I think, you know, we tend to view that trial reasonably favorably, right? It showed that there was clearly a clinical directional effect of the drug's activity. And when you look at the primary endpoint of EASI-50, on the one hand, they didn't reach statistical significance, but on the other hand, they did on things like itch, which is what would be predicted from blocking TSLP. And the final point is, when you sort of look in that era, when both tezepelumab and then lebrikizumab were in development, they were appropriately taking the right kind of risk, thinking about how they could accelerate development. And in those cases, both the tezi and the lebrikizumab phase IIa were both combination trials. With the drug and topical corticosteroids being allowed, and what you see in both trials, although lebrikizumab did hit on its primary endpoint in terms of significance, when you look at the datasets, they actually look remarkably similar to one another in terms of effect sizes, et cetera. So from our perspective, it comes down to, I think, the combination therapy sort of confounded the tezepelumab study, and then lebrikizumab sort of escaped with significance. And obviously, that went on to be now an approved drug that's helping a lot of people. So we think that there's still a lot of interest in TSLP. You can see that with a lot of the bispecific programs that are coming out, sort of doubling down on that pathway, and we've seen some sort of interesting data from companies like Biosion coming out with sort of open-label, uncontrolled monotherapy trials, where you're getting reasonably good effect sizes that's unlikely to be due to placebo response alone, so all of that sort of suggests TSLP is sort of live and active and remains a valid target, and we would agree. And then for alopecia, kind of the mechanism action there, rationale? Yeah, it's Jodie. I can pick that up and then open to you and Sheila. I think whereas Jodie has mentioned a number of times that atopic dermatitis has really become much more about the sequential immunophenotype of Th2 and Th1, alopecia is much more focused on that Th1 immunophenotype, and specifically, that CD8+ T lymphocyte, which is driving a lot of the biology in the hair follicle. So although we have very high confidence and probability of success for both, based on the preclinical data, they are different from one another, and they represent sort of different aspects of the biology and the underlying thesis of bempikibart. But, in the case of AA, reiterating, it's primarily, not exclusively, but primarily about more of a Th1-driven element, versus AD, where we're getting both Th2 and then Th1. Anything else you want to add, Jodie, or good? I think he nailed it. Awesome. Okay. Yeah, and I guess from a clinical experience perspective, I think, Sheila, you talked a lot about the well-behaved nature of the molecule, your ability to sort of hit that target dose that you want to. I guess maybe thinking about the phase II trials, can you talk about, you know, dosing, and I guess specifically in AD, you know, the dose selection work that you've done to get confident into the second part of that trial? I think, Jason, you can take this one. Yeah. Yeah, and then, Sheila, if I miss anything? Sure Since you're sitting right next to me. Alex, it's a great question. I think, I'll reemphasize where you landed. We have been remarkably surprised about how well the molecule is behaving. When you look at the preclinical pharmacology models that were built by BMS, the modeling predicted, in many ways, almost exactly what we were seeing clinically. So to summarize, as Sheila mentioned earlier, in the low mg per kg range, and for us, that's, you know, in the one to three mg per kg range, we're getting full receptor occupancy and signaling inhibition, with ample margin to spare. Second, the PK thresholds that we're targeting clinically, which are about five microgram per mL systemic, are about a factor of somewhere between five and seven higher than what we need to get full receptor occupancy. And that, critically, doesn't appear to differ at all between healthy volunteers and patients with atopic dermatitis, which is now getting into that sort of Part A of that AD study. We were able to show that those dosages get us the pharmacology we want, and importantly, the safety and the tolerability profile mirrored pretty closely what we were seeing in the healthy volunteers. So nothing about having AD sort of popped up and said, "Oops, you know, the safety profile tolerability looked different here." And including that ADA profile that we've commented on a number of times in prior venues, that we do see ADA, but where we do, it's generally very low titer and does not impact pharmacology or safety. That's the kind of thing that we saw on that dose selection study. So we were able to take those data, share them with the relevant regulatory authorities, and obviously, because we're using that dose, everything sort of passed muster, both from our perspective and from theirs. And we were able to carry that 200 mg flat dose forward into both clinical trials. Which brings me to the last point. You know, we obviously monitor safety and pharmacology as part of our sort of routine regulatory obligations, and what we see on the blinded basis with pharmacology is that the drug is behaving, again, as we had hoped it would behave. We're achieving the exposures we want. We're getting receptor occupancy where it should be had. And, you know, if the goal is to give the drug its best ability to sort of show itself on an efficacy side, I think the pharmacology is cooperating really well there. Great. And then maybe talking about the Part B of the phase II in atopic derm, can you talk about that design? How it compares to other contemporary studies and sort of your view for a positive outcome? Yeah, I think, Alex, great question, and Lee, if I, you know- Yeah, please, please. Sure. It's very similar in many cases, if not identical, to contemporary Phase IIa clinical trials in AD. The three elements are, our population is moderate to severe and the thread, the defining characteristic there are the same as other trials, EASI, BSA, and IGA thresholds. Second, very similar to other trials, it's a monotherapy trial. Topical corticosteroids or calcineurin inhibitors as companion therapy are not allowed, and I think we have very good investigators that understand the way those trials are supposed to be run. And third, the primary endpoints, again, are, and the key secondaries are very similar, if not identical, to what other trials are both doing and reading out on sort of simultaneously. In our case, it's a change in baseline of the EASI score a s our primary endpoint, assessed at week 14. Again, very typical for modern trials. And the key secondaries are all about proportion of patients that hit the relevant EASI thresholds or IGA thresholds, and we, like others, intend to be sharing those at the time of our top-line data. Yep. Lee, anything more to add? No, that's exactly right. Current timing guidance here? It's the fourth quarter. We've guided. Yeah, fourth quarter. Yeah. Okay. And I guess from a bar for success for moving into phase III, what do you feel like you need to show to have a competitive profile moving forward? Is comparability to standard of care enough with a new mechanism, or do you need to show something better? Lee, do you want to start? Sure. So your question was around a bar for success, and you mentioned novel mechanism, and I do think that that is a very important point, you know, particularly in atopic dermatitis. Given that there are a lot of drugs under development really pushing the Th2, and we are quite novel, as we've talked about earlier on with the Th1 and Th2, and just having a novel mechanism is what doctors and patients really are clamoring for. We might look at contemporary trials, which would be most relevant in our case. It's a bit difficult to compare different trials conducted at, you know, different time points, you know, over the years. So you might look at, for example, one of the more recent trials in atopic dermatitis is an OX40 ligand. They, over the last two years or so, have reported out a phase IIa and a phase IIb, and each of those, they were about a 30% placebo-adjusted mean change in EASI. You know, clearly, if we hit that, if we are at a 30% placebo-adjusted change, we would be incredibly confident that we have a drug. And again, just to reiterate how important it is, a drug with a novel MOA. Yeah. So that's atopic dermatitis. I don't know if you also asked about alopecia, but we— No, I wanted—b efore we talk about the bar there— Okay. I just want to talk about specific nuances of that trial design related to, you know, contemporary studies, and then we can get into the bar. Yeah, Alex, let's dovetail directly into that. I just want to, I'd like to add on one final point. Sure Obviously, I completely agree. We cannot emphasize enough this alternative MOA. It's not just about picking a number that mirrors an effect size. So we can come up, and obviously, you all can come up with any number you want. So yes, the 30% is the meaningful marker, but what's more meaningful is that the field has acknowledged with the OX40 ligand data and the OX40 data from Amgen, that we're moving away from narrowband pharmacology targeting of individual cytokines, IL-4, IL-13, and we're moving up to more broadband T cell inhibition, where you're getting a more kind of full ensemble of cytokines, in our case and in the OX40 ligand case, that are addressing both Th2 and Th1, and what do you get with that, well, you get a very good efficacy response when you look at skin clearance. You get movement on itch, which is really important. And in the case of the OX40 ligand data, you're seeing a remittive potential sort of inaction that's bringing the potential for much less frequent dosing. We couldn't agree with all of those points more strongly, and it's exactly the kind of thing that we're hoping to also do with our datasets. A new MOA, targeting a T cell, getting a more extensive and complete efficacy response, and at the same time, being able to move into once-monthly or even less frequent dosing. That's where the field is moving, and we think that we'll have an opportunity to, you know, with our data, to contribute to that movement. Great. Super, super helpful follow-up there, and then, I guess pivoting to alopecia areata, can you talk about that trial design, how that compares to what's out there, and what you're thinking about for bar for success? Yeah. So, I'll start with compared to what's out there, and I'll let Lee comment on, and Jodie, on bar of success. The good news and the bad news is there's not a lot out there. Yeah. So it sort of limits what we do. We obviously have two approved JAK inhibitors. Our perspective is that the trial that's most relevant of the two is the ritlecitinib phase IIa trial that was run by Brett King, who's also our primary investigator. That study looked at the same population, SALT scores of 50-100, which is called severe and very severe, in the case of SALT, 95-100. It's the same duration of disease in terms of the current flare, total duration of disease between four years and eight years, for example. And critically, the endpoint was the same, 24 weeks. We cannot emphasize enough. We take great effort, Alex, in every meeting that we have to talk, that when you measure the endpoint in AA, matters very much. And in the case of alopecia, twenty-four weeks is sort of the bare minimum where you'd wanna be doing that, and that trial offers a direct comparison, in the case of a JAK inhibitor, with the same endpoint assessed at the same time point. In terms of, you know, how that translates into how we're thinking about where our data would play, I'll turn that over to Lee and Jodie. Sure, and, again, I think just to reiterate, it's critically important to look at the relevant time points as you think about the data readout. Because some patients will continue to grow hair past the 24-week endpoint, which is about as short as you can go in alopecia. Many trials go beyond that, 36 and 52 weeks, and so it's critically important to compare apples to apples at that 24-week endpoint. There was one JAK inhibitor, at least that we are aware of, that did show data at 24 weeks. They showed about a 31% placebo-adjusted mean change in baseline SALT score. You know, obviously, the JAK inhibitors, as you know, we know across t he class, have, you know, significant safety and tolerability issues. When you talk to the KOLs, you talk to patients, doctors who treat them, having safer, better-tolerated alternatives is absolutely critical. And so, you know, we think that there's some margin there, and as we've talked to sort of the key KOLs, we would be very comfortable, you know, if we saw a mean placebo-adjusted change in SALT score north of 20%, to say at 24 weeks, this is —t his drug is doing something. It is having effect, an effect. You know, recognizing, of course, that, you know, there will be differentiation on the safety and tolerability profile. Recognizing it is a biologic, it's possible that, you know, it could take a little bit longer than a JAK inhibitor, but that would be really indicative that we have a drug here, if we saw a change like that. And again, you'd expect the placebo response to be quite modest in this population. Yeah. I think the final point just to make there, that Jason mentioned, and this is also very important, is that this is the same population as what has been studied in the JAK. So this is the severe alopecia patient population, as defined by a baseline SALT score of 50. So 50-100, that is the severe population. Of course, also including the very severe, of 95-100. Yep. And this trial also, fourth quarter, any granularity around which comes first or the same time? So we're expecting these are gonna be likely simultaneous that we'll have them. But, you know, obviously, it depends on final patients into the follow-ups. But given they recruited about three months apart, and the endpoint is three months apart, we think it is likely to be simultaneous. Great. I did wanna spend the last few minutes here talking about your complement program as well. You know, I guess at a high level, you know, how is this program going to solve some of the challenges of sort of broadly inhibiting the complement pathway? Yeah, I think high level, and I'll start, and then I'll hand it off to Sheila to go into more depth. The goal really is to take a targeted approach to the diseased tissue, as opposed to doing a systemic blockade, which has been historically the key focus. And so that was really kind of the origins of the platform that we built, was to really direct it that way. I'll let Sheila give you a little more detail from there, though. Yeah, you know, it's really built around this concept that when complement does become activated and drives disease, the bulk of the reason is that the complement becomes activated, tethered on the surface of cells. And e verybody else really has gone after systemic blockade of the complement system in order to achieve that in the tissue, and we just think it's a very inefficient way to go about the problem. So this lead molecule is really focused on the idea of bringing in a fragment of a protein, factor H, that naturally exists in our body and keeps that complement system in check, otherwise we'd have self-attack. You know, lots of preclinical data across a wide range of models that demonstrates we can shut down complement activation in the tissues at really low doses administered once every week, and potentially less frequent dosing intervals. And that really set the basis for us to understand drug exposure levels associated with tissue PK and PD, and we're carrying that into the clinic. Yeah, and then can you talk maybe at a high level about where you're at in the clinic, your approach to the renal basket study and your AAV study, and timelines as well? Sure. So Alex, just to clarify, is your goal on the approach to talk a bit about the indications or the kinds of flavor of data? What's on your mind? I'd just like, you know, high level. We have a couple minutes here, so just sort of high level of where you are today, and the path forward maybe. Right. Yeah. I think Jodie, I'll start, and then turn that over to you for timelines and everything. I think, Alex, we've got— Sheila just mentioned a large body of data- she said, that supports the key thesis, and it's simple. You can give a drug, in this case, ADX-097, which is an alternative pathway convertase inhibitor. You can give that drug at dosages which lead to no systemic exposure that would be associated with impairment of systemic complement. And at the same time, you're going to get full inhibition of complement at the level of the tissue, and sort of catalytically inactivate those convertases. When you think about which diseases might benefit from a profile like that, you're thinking of two sides. One, where do I want more efficacy? So you're talking in diseases that could be quite acutely severe, for example, lupus nephritis, ANCA-associated vasculitis. Or on the other extreme, patients that are already under such a high burden of medication therapeutics, that they already are at extreme risk of infection and infection-related complications due to those drugs. If we could add another therapeutic that might help with efficacy, but doesn't augment that infection risk due to those other drugs, well, that might be quite an interesting value proposition. So we have thought about the indications, above all else, from that perspective. Clearly, there's other benefits, of the way we think about them, regulatory approaches and timing to approval. But at the core, is could we deliver a therapeutic that has a lot more efficacy to offer than what's out there today? And we think the approach absolutely confirms that that's possible. We've seen data from Apellis now coming in that's showing when you get a very good complement inhibitor that can act, you can get a lot more proteinuria response that's been put on the table. And more importantly, when you're thinking about diseases like ANCA-associated vasculitis, on the one hand, absence of treatment, it's fatal generally within a year. On the other hand, the treatment, the most common complications in the first year, is that you get sick or unfortunately may have morbid events due to infection and infection-related complication. We may not be able to fix that. We'd like to, but at a minimum, we don't wanna contribute to that problem. Great overview. Yeah, appreciate that, Jason. And then, you know, just sort of next steps for this program and timelines. Yeah, so expectations, you know, the renal basket is underway now. We expect to provide an update on the status of that, and some early data at the end of this year. And then what AAV will be kicking off next year, we're fully funded for the datasets that'll be coming over the course of the year that follows, with both programs expected to read out by the end of next year. Great. Well, always appreciate the discussion with you all, and thanks for joining us.