Everyone, thank you for joining our Piper Sandler Healthcare Conference. It's day one of our conference. Excited to be having the team from Zura Bio. Lots to discuss over the next 25 minutes. Three different assets with each pipeline opportunities behind them, so let's see how much we can cover over the short period of time. I think, maybe we have to start off for investors that are listening to the webcast. There's a big indirect catalyst expected from Q32 here of TSLP and IL-7 and AD and AA. Would love to hear your thoughts around the data that comes out. What is your expectation, and what is your preparedness in terms of kicking off your own program? So how do you foresee sort of this upcoming indirect catalyst? Yeah, thanks. Yeah, it's great to be here as well. Thank you for the opportunity. We're excited to see, you know, both data readouts in AD and AA. Mechanistically, we see the rationale for IL-7 and TSLP in both AD and AA. You're addressing both type 1 and type 2 inflammation. So the opportunity to have a bispecific approach in a disease where there's still a lot of unmet need makes good rationale. I think the things we looked at first were the design of the study that Q32 is doing in AD. When we think about a study for AD, there's two or three things that we would do differently. Ideally, you wanna do a 16-week study so that when data's compared, it's like to like. That's the first. Secondly, it's helpful to consider loading doses in AD. Mm-hmm. and third, ideally, you wanna test multiple arms. Mm-hmm. So I think when you look at the AD data that comes out from Q32, it's good to have the perspective that it's 14-week data. Mm-hmm. There's no loading doses, single arm, etc. I think most investors will look at the EASI-75 delta and wanna see something in the range of OX40. Mm-hmm. Probably the ligand. I think anything within a range of 20-30 becomes attractive and compelling. Then you wanna look at some of the finer points of the detail in the study to understand, could you be better? Mm-hmm. So what we do in background is start to do study design for any of these potential indications, whether they're UC or AD or AA. Mm-hmm. That includes early protocol work. Mm-hmm. Design of the study, costing out the study. Mm-hmm. Some regulatory interactions. Mm-hmm. All of those things that are relatively low risk, don't require a lot of capital, but allow you. Mm-hmm. Allow you to be in a position to execute a study. If we move forward, we submit an IND. Mm-hmm. Likely be able to initiate a trial in probably two quarters in AD or AA. Okay. And then, as we are expecting the data, is there a treatment effect feeling that you wanna see, or a minimum that you wanna see to say, you know what, this warrants further development and capital? Or how do you think about that? I think the company has communicated what their bar for success is, but maybe what is. I think the numbers that they've shared are. Mm-hmm. Are reasonable. Mm-hmm. I think when you look at antibodies, then again, I think an important question that you'll really wanna take a look at is if you look at 14-week data. Mm-hmm. The trend for response is improving or increasing. Mm-hmm. Since the initiation of the trial, you likely would see an improvement at week 16. Mm-hmm. In 2024, etc. So there's gonna have to be some additional analysis. Mm-hmm. With this study because of the design, but you'd wanna see something that was in range of the OX40 readouts. Mm-hmm. And how are you thinking about AA, which is also a lucrative opportunity? Yeah, I think AA's really it kind of gets forgotten a little bit. Mm-hmm. So in alopecia, we know there's two areas where we think will have a more beneficial effect. One is the relative reduction in CD8 cells for teplizumab, as well as the TSLP inhibition and activity on dendritic cells around the hair follicle. So anything they've guided toward kind of a SALT20 of maybe 10 to 15. Mm-hmm. Ideally, you'd wanna see something 15. Mm-hmm. Or north of 15. While there are JAKs that are approved, they're still used infrequently. Yeah. And this is a market where additional therapies are needed, and the opportunity is robust. So we're encouraged to see the data in both of those indications. Okay. Very helpful. I know I wanna also, given that there are three assets and maybe just one last question on how will you base your dosing analyses in terms of dose selection and loading dose? You know, if you're not looking at receptor occupancy, what measures are you gonna be evaluating closely to make your decision? Yeah. Receptor occupancy is one that you would look at. Yeah. It's a fair one. Also, pSTAT5 inhibition. Mm-hmm. It's another, but the way you wanna look at the overall effect you're having against T cells. Mm-hmm. Whether it's CD3 or ILC or CD4 or CD8, and also run a PopPK model. Mm-hmm. Understanding your effect of occupancy in the blood is important, but skin is more important. Yeah. 'Cause these are skin diseases. So some of the additional work we do. Yeah. is to understand that. When we looked at the type 1 diabetes study for teplizumab. Mm-hmm. At one, three, and eight milligrams, receptor occupancy looks the same. Mm-hmm. But the effect of the drug is different. Yeah. You know that there's an effect that you're seeing beyond just that receptor occupancy. That's part of how we would determine our dosing strategy. Okay. Perfect. Would love to now spend time on tibulizumab and systemic sclerosis and HS. I think let's start with SSc. I think a lot of investors clearly understand that there's a big market opportunity. However, it has quite a bit of failed studies. I think you guys have been incredibly thoughtful in designing your trial. Could you talk to us about learnings from past failed studies that were incorporated into the current design that ensures a high POS of success? Yeah, I think the most important is, do you have validation of the target? Yeah. Right? And some of those prior phase two failures. Mm-hmm. They were novel agents that were. Yeah. Being investigated that hadn't demonstrated effect in the disease. In the case of tibulizumab, both IL-17 and BAFF have demonstrated effect. So I think that's rather unequivocal. I think the question is whether or not there's an additive effect that you might see from this combination approach. The additional work, though, that we've done is to make sure that we've selected a CRO. Mm-hmm. that is well-established and has conducted. Mm-hmm. Successful studies in SSC. We've done that. The second is to identify sites that have successfully done studies where the assessors are certified and trained, particularly in skin. We've done that, and the third is to make sure that we include patients who have less than two years of disease. Mm-hmm. When you look at some of the historical studies, part of the challenges has been you're getting patients who are more late in disease, and the ability to separate on skin becomes harder, more difficult. I think the final inclusion that we have is the stable background therapy of at least 12 weeks. Mm-hmm. And some prior failures. You see that stable background therapy might have been four weeks. Mm-hmm. So you didn't see the full effect of the drug and that it influenced the placebo arm. We've tried to remove all of those known risks. Okay. And what did you power the study for? And the primary endpoint is the mRSS, so. Yeah. What do you wanna see? What's considered clinically meaningful? And then, placebo is also one of the more difficult things to manage. If you could just talk about what's being done to control that. Yeah. So the biggest control that you have on the placebo, there's really two. Mm-hmm. One is the stable background therapy. So that you're not capturing patients while they're improving who are on placebo. And, right? Disrupting your delta. The second is to make sure that the assessor's really not ready to read and conduct a skin score. In terms of it's 80% powered to show an MCID of between three and five. Mm-hmm. that would be clinically meaningful. There's a number of exploratory endpoints that are also in the study around FVC, CRIS, and HAQ-DI. Mm-hmm. That will help inform the size and design of the phase 3 trial. Okay. Very helpful. Timing, just quickly on enrollment completion, when do you need to finish enrollment to deliver data? Yeah, so the guidance that we've given is these studies typically take around five quarters to fully enroll. Okay. We would expect to have last patient in Q1 of 2026. Mm-hmm. The study's 24 weeks. Mm-hmm. It yields data at the end of 2026. Okay. And I think for investors, I know they're right now very Q32 focused on indirect catalyst. Past that, which is imminent here in December, when we look in 2025, what are the key readouts in your view that both on the SSC side or the HS side that are gonna be really important for read-through to the stock? Yeah, I think the most meaningful read-through in 2025 will be Novartis's BAFF. Yeah. ianalumab. That's part of an overall platform study. Yeah. They have on hidradenitis. Mm-hmm. They've guided a readout for that data in 2025. Yeah. They've not given the quarter yet. They tend to update on a quarterly basis. Yeah. And they tend to share the data at a derm conference. Mm-hmm. Perhaps AAD. Yeah. That's when the BTK data came out. Yeah. or perhaps later in the year, EADV, but that we expect that in. Yeah. 2025. That would, I think, every investor's very familiar about IL-17 and HS, so it will be a validation of, you know, past activity in this disease that could be really important. Where are you in terms of your developmental plans kicking off the HS study? You know, what is on the agenda to get that up and running? Yeah, we've selected a CRO. Okay. We selected a, I think it's fair to describe them as a boutique derm CRO. Mm-hmm. A CRO that has a lot of experience in skin studies. Mm-hmm. It's largely a North American study, predominantly. Mm-hmm. So the CRO is in place. Right now, what we're working on is we've submitted a pre-IND as well. Mm-hmm. Based on the feedback on the pre-IND to the agency. Mm-hmm. Then an IND submission will be Q1 of 2025. Okay. It'll be a new division, derm, that would enable us to start the study in Q2 of 2025. The final work for us right now is really around the final design. Yeah. Of the trial. The trial will have two active arms, one placebo arm, and at least one arm of that trial will have a loading dose in it as well. Mm-hmm. We're still doing some work on 12 versus 16 weeks. Mm-hmm. To determine what's the better endpoint. Mm-hmm. Given some of the noise over the last six trials. Yeah. Outside of that, we would expect this, you know, the IND clearance to be the key gating factor here. Okay. And what are you projecting in terms of enrollment timelines and top-line data? Yeah, so the study starts after SSC. Mm-hmm. But the study, whether it's 12 weeks or 16 weeks, is shorter in duration. Mm-hmm. The population is larger. We actually expect study readout prior to SSC. Mm-hmm. Study readout right now, we're guiding toward Q3 of 2026. Okay. So likely a quarter or a couple months prior to SSC. Okay. That's important, important too. Why not are the doses that you're gonna be selecting in the HS study gonna be the same as in the SSC study, or is there gonna be some modifications in terms of? Yeah, it's a great question. One of the real learnings we've had is around. Mm-hmm. When we look at the historic models that Lilly had developed for this product, we see an opportunity to dose higher. Mm-hmm. Essentially a no-regrets dose. Safety profile tox looks great. Mm-hmm. At really high doses. So in both trials, we've increased the dose that we're using in both. Mm-hmm. In the HS trial, we'll be at the high end of the range. Mm-hmm. The study doses in phase 1 studies were 30 milligrams to 300. So it's reasonable to assume that there'll be some one arm where patients may be getting 600 milligrams per month. Okay. And part of that, yeah, as I should just add, was based on that PopPK model. Mm-hmm. Where we really wanted to make sure that we were getting broader skin exposure for this drug, for BAFF and IL-17. Mm-hmm. If you're under 300 milligrams, you just can't achieve that. Okay. And I think, for both SSC and HS, I think in SSc there's been quite a bit of data on both, you know, IL-17's role, but then how much BAFF contributes to the skin as well as other manifestations. So could you talk about the genetic and mechanistic work that was done and the background to really lead you to say, "We select, you know, SSC and HS, and here's why"? I had the pleasure of meeting Vicki last night. Yeah. Who's a phenomenal T-cell expert, so. Yeah. She can come and help you with on mechanistic, but would love for you to kinda talk about that because I think that could be helpful for investors. Yeah, I think genetic data and preclinical data is always helpful. Yeah. But I think it is a little less necessary. Yeah. When you have clinical data. Yeah. That's the piece that I would focus on is that it's known that BAFF is in dendritic cells, right? Yeah. When you actually take a biopsy and look at the tunnels, you can see the presence of BAFF. Yeah. It's different than healthy subjects or AD subjects or psoriasis, so it's exclusive. Mm-hmm. To HS. That's the first. Yeah. There's a number of B cell-reported data endpoints now that also support the role of B cells. Mm-hmm. CD20 with rituximab, fostamatinib. Mm-hmm. And BTK inhibitor as well from Novartis. And there's also a fair amount of case studies, right? So the literature and support for depletion or neutralization of B cells is strong. Mm-hmm. It's clinical support. Yeah. the BTK data we think is the most meaningful. Mm-hmm. As a readout to BAFF. It's not a perfect readout. Yeah. But it's a reasonable read-through. Okay. And in terms of given that you highlighted Novartis's, you know, BAFF depletion could read out in 2025, could put the mechanism on the radar and validation in HS, is there a reason to believe that it couldn't? I think it's exciting if it works, but is there a reason if it doesn't work, can we conclude that maybe BAFF is not alone needed? We need IL-17 activity. Like, how should we be thinking about sort of, you know, in a situation of it could if it's positive, great, dual mechanistic potential, but is there a risk that it may not work out? And what would that read-through be for? Yeah, I think that, so with HS, part of the compound is validated through 10 different studies. Yeah. Run IL-17, so you know that BAFF is present. Yeah. In the lesions, in the tunnels. Yeah. So it's reasonable to assume there's some benefit. Mm-hmm. Whether BAF by itself would be sufficient, I think it's harder to answer. Yeah. We won't know until we see that data. Yeah. But our approach is IL-17 plus, right? Right. And when we talk with experts in HS, what they talk about with us is the heterogeneity of the disease. Mm-hmm. That while IL-17 has been beneficial. Mm-hmm. It's still, you know, it's. Yeah. 15%-20% in terms of the EASI-75 delta. Yeah. It's good, but there's a lot of room for improvement. Yep. Perfect. And is there any competitive readouts in SSC in 2025 that we should be flagging, or your data will be one of the? Yeah, it's none that I'm aware of. Yeah. So when we look at kinda the landscape for phase 2, phase 3 studies, it's 26 and beyond. Yeah. right? These are orphan diseases. Yeah. Endpoints are long. Yeah. So it takes a little longer to get the data. Mm-hmm. There may be some data that's released between now and then. Yeah. phase 1 data, etc., some additional CAR T data. Mm-hmm. but nothing right now that we're looking at as either a read-through or a competitive event. Okay. Very helpful, and just maybe a few comments around for investors who are new on SSCs, like, what is sort of the regulatory path forward, registrational path? Like, what is what, what's the sort of size, duration? Yeah. Endpoints that are important? Yeah, it's an orphan disease. Mm-hmm. And the benefit of that is you, you know, you can do a single study. Mm-hmm. Single phase 3 study. So the phase 2 study is largely used to inform your power and assumptions and your sample size. Mm-hmm. Most phase 3 studies are 300 patients. Yeah. Roughly. That's what you need to see in effect in lung FVC, so we would expect to have a very similar treatment from the FDA. Yeah. I think the only open question on phase 3 is whether or not there is a change to the modified. Mm-hmm. CRIS that the agency uses. Mm-hmm. There's been some discussion now. Yeah. In the panel of experts, so there may be some changes. Yeah. Part of the historic challenges in this disease is not necessarily, and Vicky and I had this conversation. Yeah. Is it the drug fail or is it the wrong endpoint? Mm-hmm. So part of what the regulatory authorities always try to do is to try to make sure you're measuring the right outcomes. Mm-hmm. To determine whether or not a drug works. Mm-hmm. So it will still be the components of the CRIS, that won't change. Mm-hmm. But whether there's different weighting or influence by anyone. Yeah. Could. Can a drug get approved on just skin manifestation alone without having an impact on the lungs, or does one need to show benefit on both sort of manifestations? No, I mean, Actemra is that example, right? Yeah. So, in n it was funny. It was kind of an artifact of the. Mm-hmm. focuSSced study, right? Yeah. They were able to show benefit in lung and. Yeah. Some analysis in skin as well. You can get approved for just one. Yeah. I think the challenge is the need right now is for something that treats the whole disease. Yeah. So anything that just treats one component is going to be limited. Yeah. in its attractiveness and commercial uptake. I think for investors, they have a good understanding of IL-17 blocking activity in terms of the benefits it can have in skin, but maybe what's a little opaque is how it could also mechanistically work on the lung manifestation. Maybe if you could talk about that, is the study even powered in your phase 2 to show that? Is it an exploratory? Would love for you to, like, talk about. Yeah. Yeah, so both 17 and BAF play a role in inflammation and fibrosis. Yeah. Across all organ systems. Mm-hmm. They're both associated with the progression of. Mm-hmm. SSC as well as the severity. Mm-hmm. There's good evidence that supports that. Given the size of this study, you're not likely to see a significant endpoint in FVC. Yeah. Lung function, right? Right. So part of the way that you try to mitigate your effect in lung is through high-res CT. Mm-hmm. The image of the lung. So you can see a picture of the lung. Yeah. You can understand how much fibrosis is in the lung. Mm-hmm. Whether or not you're improving that fibrosis, that's your endpoint, and it's highly concordant with FVC. Mm-hmm. So here you have the ability to show both structural change. Mm-hmm. And then, more importantly, a capacity change in the lung's ability to function. So that's, that's really the. Mm-hmm. The benefit of the HRCT. That'll be part of the phase 2 study and the phase 3 study. Okay. Perfect. Now that we have a few minutes, five minutes left or so, I would love to also spend time on your third asset that doesn't get a lot of love from the street, which but it has a key readout, indirect readout next year that you guys are actively monitoring. So I guess let's start off your IL-33. What is the differentiation of your antibody versus others that are in development? Part one. Part two, if you could educate investors, what will we see in the competitive landscape from this mechanism that you think are gonna be that you're tracking very closely? Maybe we'll start there. Yeah, there's two phase 3 readouts in COPD and Q2 of 2025. Mm-hmm. Roche has a product, astegolimab that is. Mm-hmm. An ST2 receptor, so it's bound to the receptor. Mm-hmm. It works against the receptor on the ST2-dependent pathway. Mm-hmm. So it's not an IL-33. Yeah. But it, you're right. Right. Kinda turns off the light versus the fuse box. Sanofi Regeneron have a. Mm-hmm. IL-33 in development for COPD. Mm-hmm. Also, reading out phase 3 in Q2 of 2025. So the Roche product is ST2 receptor. Yeah. So you're working on just one side of the IL-33 pathway. Yeah. The product from Sanofi is IL-33 specific. Torudokimab influences both IL-33 as well as RAGE. Mm-hmm. RAGE is not a term that, you know. Mm-hmm. is used a lot. It's a pattern recognition receptor that is responsible for inflammation through a number of different cytokines, including TNF and IL-6. Mm-hmm. In the case of torudokimab, independent. Mm-hmm. Independent pathways are both downregulated. Mm-hmm. So you could potentially see a better effect. The final comment on that is Lilly did do some comparative work. Mm-hmm. On the potency of itepekimab versus torudokimab in GM-CSF. Mm-hmm. In that experiment, Torudokimab was far more potent. Mm-hmm. So you potentially have a more potent asset, with broader. Mm-hmm. Application that could move directly into a 2b study. Upon COPD data from both of the studies, would you be then I guess, again, what would you wanna see in those? COPD's a big market opportunity, right? Yeah. What treatment effect do you wanna see to say, you know, "And we're committed to going to COPD"? Are there other smaller orphan indications for this mechanism that could also be fruitful? How do you think of this? Yeah, I think so the IL-33 is so it lends itself to T2 or 3. Mm-hmm. Multiple other indications, but the torudokimab has an ability to have a linker antibody attached to it. Mm-hmm. So, for example, if you wanted to create another bispecific. Mm-hmm. You could have an IL-33. Yeah. And an IL-13 or an IL-33. Mm-hmm. And a TSLP, and you could think about a broader range. Yeah. Of diseases where you're getting a, you know, broader effect. Mm-hmm. That's one. COPD, if both of those products hit the static endpoint or of acute exacerbations lowering. Yeah. That's gonna be attractive, right? Yeah. Because there's really no choices for those patients today. Right. So we'll wait, we'll see the data. We work in background on study design, protocol development, just like we do for. Mm-hmm. AD or AA. Yeah. Or any other disease. And then we wait to see the data to validate. Mm-hmm. And then make a decision as to whether or not to move forward. And that asset is the one that generates the most interest. Yeah. Interest for the company. Okay. So, yeah, continuously so. There's a lot of interest because IL-33, there's a bit of a renaissance there. Yeah. Also, the ability to link it to other antibodies makes it appealing. How, let's say, fast forward when in 2025, do you recall when they've guided? They've guided Q2 of 2025. Okay. Both companies. Yeah. They're right on top of each other. Okay. Excellent. And, let's fast forward into Q. We get the data as positive. How soon are you ready to enter the clinic and start? Yeah, it's generally. Phase 2b? Generally, any time that you, it's at least two quarters. Yeah. Okay. Right? Because of the IND process. Yeah. The contracting process with CROs. Yeah. Feasibility analysis. Yeah. IRBs, those pieces. Yeah. So when the data comes in, we'll evaluate the data. Yeah. We'll compare it to the internal benchmarks. Yeah. That we develop. Yeah. In combination or in background, we're also looking at other potential indications. Yeah. Right? So we have the optionality of potentially pursuing COPD. Yeah. Or looking at those other indications if that data's not compelling. No, that's great. And do you hope, I guess, with three different assets and they have a pipeline, can you talk to us how much what is the prioritization? How much capital and time is spent across these three different assets? Yeah, the bulk of time and capital is spent on ZB-106, the lead asset. Okay. Yeah, I mean, it's kind of, you know, our first job. Mm-hmm. Is the SSC study. Our second job is the SSC study. Yeah. Our third job. Yeah. Getting SSC right. Yeah. HS, right, are critical. Yeah. Right? That's most of the valuation of the company. It's right? Yeah. Where the capital was, was brought in as well. So the value of the other data sets or the other molecules is to look for that clinical validation. Yeah. Right? Once there's clinical validation, can you design a better study with a more active agent to produce a better result? Yeah. So limited at-risk capital is used to do that. No, that's very helpful. I think it's helpful to put into perspective, right, like past the Q32 competitive data, you know, you're headed into HS BAFF data from Novartis, and you're gonna have two COPD readouts for two of its assets for which you're not getting any credit for. Yeah. Then by the time we go into the back of 2025, you're gonna be less than a year away from your own readouts in SSC and HS. As your covering analyst, it's kinda like a nice stock setup here. Yeah, I think that the look, we have to continue to tell the story. Yeah. Show the science, right, and continue to engage with investors. Mm-hmm. But when you look at the interest right now in bispecific antibodies. Mm-hmm. Across autoimmune disease, I think we're on the leading edge. Mm-hmm. We have three. Yeah. They're all unique in terms of the role that they play. Mm-hmm. And all of them, to some extent. Mm-hmm. Have some validation as well. Mm-hmm. So it allows us to move quickly into two phase 2 or phase 2B studies. Great. It's been a pleasure having you at the conference. You're gonna have a very packed schedule today, so, thank you again for you and your team for being here and part of our. Yeah, thanks, Yaz. Yeah. We appreciate it. Thank you.