Everyone, thanks for joining us here at the Leerink Partners Global Healthcare Conference. My name's Thom Smith. I'm one of the Senior Biotech Analysts here at Leerink. It's my pleasure to welcome our next company to the stage, Q32 Bio. Happy to be joined on stage by CMO Jason Campagna, CSO and founder Sheila Violette, and CFO Lee Kalowski. Thank you to the Q32 team for joining us. Thanks for having us. Jason, why don't you go ahead and kick us off and maybe provide some kind of high-level overview, introductory comments on Q32 for those in the audience who may be a little less familiar with the story. Sure, I'm happy to. Thanks, everybody, for coming today. Q32 was founded about six or seven years ago now on a simple premise that we thought that there was a sort of better way to approach I&I. It was around this concept of rebalancing the immune system. For much of the company's history, we've had two programs, the Complement Program, which is where the company was founded. Q32 actually stands for Band 1, Chromosome 1 Band 32, where many of the complement proteins are coded. Then the ADX-914, also known as Bempikibart, which is our lead clinical program. Each of those takes advantage of a pretty basic fact that human biology is actually really good about controlling the immune system with naturally occurring endogenous elements. In the case of Complement, that was things like Factor VIII or CR1. More importantly, in Bempikibart, it's the Tregs. What we really liked about the mechanism of ADX-914, now known as Bempikibart, is that on the one hand, it gets to the affected memory T cells, which really are what are driving the underlying autoimmune condition. Also, while antagonizing that pathway, it would also be able to restore sort of functionality of the intrinsic endogenous Tregs, therefore sort of restoring balance. At the present time, we just completed, just before the trip here to Miami, we were all up in Orlando, where we had an opportunity to have Dr. Brett King present at a late breaker session the most recent updates from our alopecia areata trial, which we'll talk about today. That excitement around that late breaker submission that we had really is what underlays our recent decision to sort of deprioritize the Complement Program and really focus that instead as a sort of phase II ready asset and program, and really pay much more attention and really focus our clinical development efforts on Bempikibart, specifically in alopecia areata, which is where we are today. Lee, Sheila, anything more to add? Nope, that's great. Great, perfect. Yep. Yeah, we'll spend much more time going through the alopecia data in detail, talk about the kind of broader overall phase II experience with Bempikibart. I guess I want to start just sort of higher level, just talk about the rationale for blocking IL-7 receptor alpha. That's the mechanism for Bempikibart, the impact that you think you're having on IL-7, as well as TSLP, and maybe some of the learnings you can draw from prior clinical experiences, both with the target as well as targeting each of those kind of individually, TSLP and IL-7. Do you want me to start, or do you want to pick up from the beginning? Why don't I pick up from the beginning, and then if you have anything to add. As many of you may know, Bempikibart binds to the IL-7 receptor alpha subunit. Because of where it binds, it blocks the signal that's mediated by two separate cytokines, both TSLP as well as IL-7. What we really knew from just a very broad range of preclinical data that had been generated with the IL-7 receptor alpha antibodies is that this is a molecule that can go pretty broadly. This is mediated in part because of its ability to block TSLP and thus TH2 responses, but also to be able to inhibit IL-7. We know that IL-7 is really a cytokine that provides the fuel for pathogenic T effector cells. Really, because of this rather unique biology of this bifunctional antibody, there's an opportunity to take it in many places. When we think about what have we learned from others that have gone before us, we know that the TSLP pathway has been validated now in a lot of respiratory diseases. There's a fair amount of data and rationale for blocking TSLP in other TH2 mediated diseases that would include skin diseases like atopic dermatitis and other respiratory diseases like COPD. We also know from others that have gone in parallel with us that there are a lot of diseases that you would think about when you think about those pathogenic T effector cells. The disease indications where there's really, really good rationale include things like alopecia. We now have validating data in the clinic. OSC, who's taken their IL-7 receptor antibody forward in ulcerative colitis. A lot of other interesting opportunities might include things like celiac, type 1 diabetes, and MS. We think that there's a real opportunity to go very broadly and for which now we're sort of forging away and finding data in alopecia patients that really helps to validate this does appear to be an important pathway in those patients. Did you want to add something else? I only add one more thing, Thomas. I think the final element of your question is, you know, what have we seen in terms of biomarkers, signaling, et cetera, that got us sort of excited that this mechanism sort of is valid? I think we're the first to show what we had known preclinically had been in evidence for a number of years that this mechanism really can impact in man, both TH1 and TH2. Those are direct results of the data that we produced from our Signal AD and AA clinical trials that both read out back in December. Up until then, I think the preclinical data were really quite rich and extensive around this idea that blocking by the virtue of the sort of common alpha subunit that you can block both IL-7 and TSLP signaling and then see reductions in the relevant cytokines and biomarkers. What we were able to show in the Signal Program is that that is, in fact, the case in man as well. We think there's some really interesting implications, which I think we'll get to around efficacy and what that means. For now, we have clearly shown that those biomarker reductions are in evidence. I think, importantly, back to some of the direct TSLP antagonists, they're competitive, if not better, than what you're seeing in some of those direct TSLP antagonists. The range of the biomarker reductions we see are clearly in that sweet spot of what's been associated with clinical proof of concept and even later stage development success for a number of other drugs. That's great. Yeah, I guess maybe you could help put into context the attribute of your compound relative to some of the other compounds that are targeting IL-7. We think of the, you mentioned the OSC compound. Zura also has a compound here. Just in terms of binding affinity, half-life, some of the other attributes that you think will matter, maybe just help put Bempikibart in context there. Yeah. I think that one of the things that we could see when we looked at the early preclinical data that was generated in non-human primates, it looked like a best-in-class asset, mostly based on pharmacology. What we knew about dosing and the ability to achieve full receptor occupancy and maintain that at very low doses. We then extended that data set in our phase I trial. The PK really held up quite nicely. I think based on pharmacology, we continue to believe that we have a best-in-class asset, low ADA. There's been minimal ADA and essentially no clinically meaningful impact on PK, and able to maintain full receptor occupancy dosing once every two weeks. Now, we took a very conservative approach here that if we really wanted to be well above receptor occupancy, accounting for maybe only 15% of drug getting into tissue, we really can achieve that with a flat dose of 200 every two weeks and half-life of a couple of weeks, which is dose dependent. The pharmacology is where I think we really, really differentiated from the other agents that are going after IL-7. Got it. That makes sense. Let's talk about your phase II data you read out in December. You had a Signal AD study, Signal AA study. I want to spend most of the time on the AA study, but first on AD, unexpected, disappointing results, quite an outsized placebo effect. Maybe you just kind of frame up what the learnings were in terms of Bempikibart efficacy and some of the biomarker data that you saw there that gives you confidence that you're actually engaging the target. Do we have other hypotheses around what may have driven that outsized placebo response in that study? Sheila, how about this, I'll take the first part of that and back over to the general placebo response for you. It's hard, look, it's in candor, it's really disappointing what happened in that AD trial. There's almost no way to hide it every time I talk about it. On the other hand, there's actually quite a lovely silver lining that came out of that trial. The pharmacology, the biomarker, and the ADA data were quite simply exceptional. We put out all of those data in the public domain now. We were able to show, as Sheila just said, that the preclinical model and the phase I modeling told us that if we gave 200 milligrams once a week, once every two weeks to patients with atopic dermatitis, we will achieve exposure levels of 5 microgram per milliliter higher and full RO. That's exactly what we saw. The drug is behaving. It's an incredibly well-behaved molecule in terms of its pharmacology. It's doing almost exactly what we thought it would do from the models we built back in non-human primates. From a safety perspective, the drug was benign. There's no better complement that I could pay it than benign safety profile. It's consistent with what you would expect with a biologic. Third, the magnitude of the lymphocyte reduction is almost exactly what we had predicted based on the phase I data. We, in our non-human primates, we go up to 150 mg per kg, have no dose limiting toxicity, and never get above about a 50% reduction in lymphocytes. We knew with this range that we were playing in at around 2.5 mg per kg roughly, that the lymphocyte reduction should be on mechanism about 30%. That is exactly what we saw. The adverse events related to that were effectively nonexistent. We had a few reports of patients that had transient lymphocyte reductions and then would recover. We had no safety events related to that, no infections, no infection-related complications. Finally, we have already covered, we do not need to say it again, Thomas, the biomarkers. What came out of the trial were a host of really powerful data. Unfortunately, as Thomas, you noted, the placebo response was not at all what we had hoped it would be. Lee, maybe I will turn that over to you. Yeah, no, I think that's a really important point. The TH2 biomarkers that we're seeing are consistent with that shown by agents showing efficacy in AD. So we know that we are hitting it and we're hitting it hard. As far as placebo response rates, hard to know. We're seeing it kind of across the industry. It's a general trend. We saw it across regions. So it's sort of hard to tease that out. If you go to the most extreme, the most severe patients, we were starting to see separation, but, you know, N's going to be small. So I think, you know, we, like a lot of trials, are just seeing a higher placebo rate across the board in AD. Okay, got it. Let's talk about the Signal AA top line results from December. This was week 24. You also provided some week 26 time point there. In terms of SALT20 response, I think it was a, what was it, a 10% to 13% rate. Clearly, a lot of the excitement, I think, coming out of this program are the subsequent data cuts, some of the follow-up. You have patients who are actually coming back and asking to be put back on drug because of some of the effects that they're seeing post the study. Maybe if we could just start with kind of like that top line readout, the magnitude of that signal, I guess how you think about that in the context of other programs in alopecia. Then we'll dive into some of the other details. I know you had exciting data late breaker over the weekend at AAD, but let's start with the top line data. Sure. The context, Thomas, to the question is, what about that mechanism which gave us some conviction that AA would be an interesting efficacy story? That concept of rebalancing the IL-7 inhibition, getting at those T effector memory cells that are driving the autoimmune response, allowing the T regs to regain control. The preclinical data all point one direction. Non-human primates wrote in data one direction. Brief duration of treatments could lead to long-lasting remissive effect. Definition of long depends on the animal model. Could be weeks, could be months. In non-human primates, there's data from OSC out to a year. We believed that this remissive efficacy effect could be in evidence in our clinical trial. We built a follow-up period. With that context, back to the data. Week 24 data were modest. I think everyone, that's a statement that everyone would agree with. When compared to the known JAK inhibitors, which are the only approved therapeutics in the field, they're modest. Our view had consistently been, that's not the complete story and it's not the one that we should be focused on. We had tried and attempted to sort of guide to that beforehand, you know, with things like we didn't have a loading dose. It's a biologic. Alopecia as a disease just takes longer to regrow hair. We know that from the JAK inhibitor data. All of that being said, our week 24 data look just pretty similar to the 2 milligram baricitinib data back when they ran Brave AA1. They didn't really publicize those data because they used it to choose a dose. When you look at the change in baseline of SALT and the 30% SALT reduction, it looked pretty similar to the 2 milligram dose of baricitinib. What's more interesting is what happened after we stopped treatment is that with JAK inhibitors, we absolutely know from years of experience now, both bedside and published, that when you stop those drugs, hair will fall out. They just do. The time course is different for all patients, but generally speaking, by six to eight weeks, the vast majority of the hair that you've regrown is gone. Even when you step the dose of baricitinib down from 4 to 2 milligrams per label, patients will lose their hair. So they're reluctant, both providers and patients, to do that. What we found from week 24 to week 36 is not only a stable effect, which is in and of itself novel, but that effect appeared to be slightly deepening over time. We needed to wait for the full 36-week data set to lock before we had visibility into that. Not at all visible, Thomas, back when we put out data in December. We only had glimpses of what was happening in that post-24-week treatment period. Over the last month, we've had a series of press releases, one noting that we locked the final data set and that we had updated data for week 36. The late breaker extended that even further. We have now confirmed through week 36 that, one, we are maintaining hair. In patients that regrew hair in that trial, they are, for the vast majority of them, retaining hair. Not only 12 weeks past dosing, but we have data now past the end of study. The median follow-up is into the week 40 range. We are four or five months on average from the last dose, maintaining their hair. What we put out at AAD were those data and the additional data that we have of those, about 60% are growing additional hair. Those are the imagery that we shared at the AAD session. Putting that all together, the drug regrows hair in week 24, even in the absence of a loading dose. From week 24 to week 36, after we stopped dosing, there is a maintenance of effect, suggesting that the follicle has regained some degree of immune privilege and health. After the study ended, we had inbound requests from patients, information that they were sharing, and we now understand that effect more fully. It is still incomplete from an overall data perspective, but we understand it much better. We seem to also be growing additional hair in a large proportion of those patients. We think that, you know, the language that Dr. King used at the session in AAD was transformative, not because the efficacy, back to where we started, Thomas, not because the efficacy looks greater out of the gate than a JAK inhibitor. It doesn't. It's because the nature of that efficacy looks nothing like what JAK inhibitors bring, which really gets us to the meat of the matter. The market dynamics in AA favor biologics. It's the only INI indication where JAKs are approved and biologics aren't. Where they coexist, which is everywhere else, JAKs are good, but they're not first-line indicated treatment because there's more to it than efficacy. Our view is that biologics are coming. We'd like to think that we're the leading edge of that, but there will be more. We think that that profile, what's transformative about it, is that it sets a very different model for what efficacy looks like in a world of biologics than what you have with the JAK. That was the origin, and that's what Dr. King sort of covered at that AAD late breaker. Yeah, that's great. Yeah, very interesting signal. Maybe if you just characterize, I guess, the number of patients in which you're observing this. I mean, these are treatment effects, and you have patients who are coming back basically after the study, after they've come out of the study, asking to be put back on study, and you're in the process of opening kind of a longer-term extension for those patients. Maybe just talk to, I guess, of the original treated patients, like what's the end that's where we're seeing the signal, and then what's the plan for, I guess, getting those patients back on treatment and following their treatment course from here? Sure. I'll keep. Yeah. What we've said is that there were 12 patients that we've been in touch with who regrew hair during the trial. Of those 12, all of them have maintained their hair growth after the treatment period ended out to 36 weeks and beyond. We have, and we're still continuing to collect data, but we have gone out as late as 55 weeks in multiple patients. Okay. Of those, seven. Seven of the 12, roughly, have reported and confirmed additional growth beyond that. Those were some of the imagery that we shared at AAD. We entered that period at the end of 36 with about 19 patients. Okay. That's the sort of breakdown. Part of the challenge that we have is because it's the end of the study, not all of those patients are available for response. But of the ones that regrew hair in the trial, all of those have responded. Right. Those are the numbers that we have. What's next? We wanted to formalize that data collection, thus the open label extension that we're implementing for Part A. We had reconsented all of those patients just to get their imagery, but it's a sort of haphazard way to gather data. We'll re-put those patients, allow them to go back on Bempikibart. That should be starting, you know, imminently, which is what we were talking about at the AAD meeting. We're opening, which we'll get to, Thomas, the second clinical trial, which is what we're calling Part B. Right. Yeah, let's talk about Part B. This is another open label data set. I think you said you're targeting 20 patients, but there are some other changes that you're making within the context of this study relative to Part A. Maybe just walk through those changes and how you're hoping to really tease out, maximize the signal. The best way to think about Part B is that it's an adaptive bridge to phase III. In a sort of perfect world, if, you know, we were sort of snap our fingers and had all of the money to do what we wanted to do, we would just run an adaptive two, three. We are effectively doing that now. This open label Part B is really an adaptive trial that's intended to do three things to get us to be able to open a registrational package, a clinical trial package with the right dose, the right duration of treatment, and the right powering. There are three things. Understand the pharmacology completely. We will add a loading regimen first. Second, understand the efficacy effect better at both weeks 24 and 36. There is precedent for both as an approvable time point. What is our effect size at week 24 and week 36 if we give a loading dose? In the case of week 36, treat for longer. We know what the effect looks like now in the absence of drug. It's actually stable, as we've mentioned a number of times. The question is, if we dosed out the 36 weeks and gave a load, would that effect be even deeper? Just the direct question of what your powering for phase III needs to look like. Lastly, we want to explore this remissive effect a little bit more completely. We have a longer follow-up there. We don't, it hasn't been asked, but I will say it. We don't believe this is curative or we're inducing tolerance. We don't think that's what's happening here. On the other hand, it's not magic. It's biologically based, mechanistically clear. We are allowing those autoreactive T cells in the follicle to sort of, we're effectively enabling them to go away. The follicle is restoring some degree of immune privilege, but whatever that inciting autoantigen was, it's still there. At some point, the disease is almost certain to come back. When it will, it's unclear. The way we're thinking about that back to phase III, what's the dosing regimen? We think right now it's something on the order of you think about an induction regimen that could last months to maybe a year, depending on how patients respond. Then you would step down that dose to potentially once every two months, once a quarter, you know, potentially once every six months, depending, depending. The point of that data set is to understand what that dosing regimen looks like better. Yeah, that makes sense to me. Just, I guess, to be clear, what does the loading dose regimen look like in this Part B? We're still exploring the Q2 week dosing in Part B. We're sticking with the same dosing interval because we don't want to vary too many things. What we've done is same dose, 200 milligrams for maintenance, 200 milligrams once every two weeks sub Q. For the loading dose, we're giving a loading regimen, four doses, each dose is once a week, 200 milligrams weekly for four weeks, and then moving every two weeks. The reasons we did that are just about practicality and where we stand in the development program. We have ample headroom to go higher, et cetera, but the goal is to have 20 available patients in the study. We simply didn't want to give that higher dose and explore pharmacology that we hadn't seen yet. We'll do this. Will we add that? Eventually, absolutely we will. We just wanted to understand what the pharmacology of the loading regimen looks like in man. That makes sense. I know we're targeting enrollment of 20 patients, but it is an open label study. I guess kind of help us think about time to data. You know, I guess logistically standing this up and then time to first data point. Within the context of that first data point, like how many patients could we be looking at? What would you consider, I guess, a fulsome read on the signal? It's going to be, we've said approximately 20 available patients. Getting through 36 weeks. We've said top line data in the first half of next year. Getting through all of those patients through the 36-week endpoint. Obviously, we're going to continue to follow those patients, and we're going to do so to 52 weeks. Okay. Okay. And then, yeah, beyond alopecia, like we had always kind of thought about the applicability of the mechanism to be quite broad. Totally understand. And from a resource prioritization perspective, I think it makes sense to really focus on where you've seen the signal to date. But how are you thinking about potential of exploring beyond alopecia at this point? I'll turn that one over to Sheila, but Thomas, we will say this. It depends on who asked us. Everybody's got a bias. There are some really interesting diseases here as we open with on the biomarkers, but Sheila, why don't you pick that up? Yeah, I mean, I'll go back to what I mentioned before. You always like to go where something's been validated. The changes that we saw in the biomarkers were very respectable. I think we're really hitting the TH2 pathway hard. We think about diseases like asthma, COPD, where there could be also added benefit of hitting a T cell component. You know, genetics is really strong in diseases like type 1 diabetes and MS. That may not be the disease indication for us. We like ulcerative colitis that the original plan from BMS was to do an induction therapy trial. I think a lot of it has to do with strategically what's happening at the company, what would be percolating to the top, but there's really good rationale in many of these diseases. That makes sense. Yeah, I guess along those lines, because you mentioned the ulcerative colitis, if I could just ask you to, we've seen some top line ulcerative colitis data from OSC. I guess your thoughts on that data set and potential read-through to what you could do with Bempikibart? We like those OSC data sets a lot. I mean, we've spoken to the same thought leaders you all would speak to as well, both in the U.S. and Europe. Data are pretty compelling. You know, they're getting a change in baseline of the modified Mayo. They're seeing clinical remission at the time points they're looking. They're seeing histologic evidence of improvement in the mucosa, and they see visible evidence of mucosal healing, really very powerful. I think those effect sizes are sort of consistent with where other drugs in the field have landed. The challenge in UC is, you know, it's not for the faint of heart. It's a really difficult space to recruit in. There are a lot of drugs there. One straightforward way to think about it is that Sheila had said earlier, we believe we have a best-in-class antibody. In the case of OSC, I think we really do believe that. Pharmacologically, we're much more potent. Practically, what does that mean? We can give sub Q and we can give it once every two weeks, maybe once a month, straightforward. They cannot. Doesn't mean they're a bad drug, and it doesn't mean that they might not have a market opportunity, but apples to apples comparison, being able to give an ulcerative colitis patient a sub Q injection once every two weeks, once a month, probably plays a little better than the IV route of administration. That's a very quick way for us to sort of jump into IBD and sort of get a purchase on what that market corridor that OSC is defining and sort of jump right in there with them. Yeah. Anything? No, that's right. That makes sense. I just wanted to come back real quick on alopecia and was wondering if you could describe any of the regulatory interaction, I guess, you've had today. Like what's your level of confidence that you would be able to take these Part B data with, call it 20 available patients at this time point, and then advance that into truly like a pivotal registrational type study? Maybe we could start with just facts instead of subjective things about people's opinion. I think there are two very good programs that have reached approval in the United States. We have a third, which is sort of tied up in patent litigation, but two very clear ones. They have a couple of things in common. How many exposures do you need to move out of phase II into phase III? What's the overall safety profile of your product look like? What's the nature of efficacy? We think we're well within those guardrails of what those programs have established. We have 130 exposures and counting in our clinical program with Bempikibart across two indications, both dermatologic. We have a safety profile, I'll use the word again, benign, both nonclinical, preclinical data sets, and clinical, both incredibly important when FDA is allowing a drug to move into scale at phase III. Third, the nature of the efficacy that we're seeing is exactly the kind of thing that's the approvable endpoint. We're seeing those SALT 20 reductions. We're seeing that%, 30% patients who achieve a 30% reduction in SALT. Those are all of the metrics that FDA considers appropriate to be clearing gates to get into phase III. I think the point of these 20 patients is we're only going to be incremental on those other parts, but add additional pharmacology around a loading regimen, exploring higher exposures and treating for longer. I think we set ourselves up for a very good end of phase II meeting and opening a registrational program. Yep. Okay. That makes a lot of sense to me. Just in the last, you know, minute or so that we have, I did want to touch on the tissue targeted complement program. I know you guys had initiated, I think, a renal basket study. I'm not sure if we enrolled any patients there, but if we did, I guess what, maybe just describe like the clinical experience to date with that compound. What would you see as kind of like an optimal outcome in terms of strategic partnership? I'll take the first part of the question. It was a remarkably outstanding molecule. I would just say it was really extraordinary. Its pharmacology was exactly what we had hoped for from the preclinical models. We were able to show that the drug is an incredibly potent alternative pathway inhibitor if given in high enough doses in man. At the ranges we dosed in, where we needed to get tissue level targeting, we had no impact on systemic alternative pathway at all. Across the entirety of that dose range, up to 30 mg per kg, we're working around closer to four to five mg per kg. We had no dose limiting toxicities. The drug was really exceptional, very minimal ADA. From getting into phase II, I think we really, really liked what we had, but back to where we're at home. Yeah, I don't think we're going to speculate on, you know, a particular structure. I think we're evaluating a number of options and making some nice progress. I think all I would just say is that we have a variety of options and we're looking to maximize the value. Got it. That makes sense. All right. Unfortunately, we're up against time, but I want to thank the Q32 team for joining us and providing the updates and looking forward to the execution and the data that's forthcoming in alopecia. Thank you for having us. Thank you. Thank you for having us.