Great. Good afternoon, everyone. We're back now with Zura Bio CSO, Mike Howell, here to chat about the company in a fireside chat. So maybe I'll kick it over to Mike to give a brief overview of the company, kind of, you know, how the company was formed, and then we'll move into a fireside chat. So with that, over to you, Mike. Perfect. Thank you, Alex, for the opportunity to join you guys today. Really excited to give quite a few updates that we've had over the last couple of years. But really briefly, Zura actually started back in 2022, with a group of entrepreneurs who were dedicated to identifying high-quality molecules to bring forward into the clinic. Specifically, after we looked at in-licensing our first molecule, the idea was to find areas where we could cause paradigm shifts within medicine, not necessarily just incremental improvements, but truly paradigm shifts. And so this has actually led to the in-licensing now of three assets, a formal transition from a private company to a public company in March of 2023, and then since then, we've actually gone through and raised over $200 million to support the kind of development of these three assets as we move forward. And I'm happy to walk you through kind of each one of those assets, what they bring to the table, and how we plan on bringing those out. Yeah, that's helpful. So maybe let's start with, you know, your IL-17 by BAFF, the tibulizumab asset. Can you talk a little about that, where it came from, and I guess the rationale for going after both targets? Absolutely. So first, I'll start with a little bit of the rationale. When you look at autoimmune diseases and inflammatory conditions, a lot of these aren't just driven by a single cytokine. The human body is incredibly complex, and so as you think about the development of most autoimmune conditions, there's typically multiple inflammatory pathways that are turned on within a given individual. And so a lot of our current approaches look to us as antagonizing one pathway in particular, and this is limited, and you can see the limitations associated with that, with the therapeutic benefit of most of these therapies that have gone forward. What prompted us to actually in-license tibulizumab was the ability to go after IL-17, which is a well-documented pathway of activation within most autoimmune conditions, and BAFF, which is important to B-cell activation. Again, a lot of these individuals have autoantibodies that are produced. Through that process, we ended up engaging with the Eli Lilly team and, through a number of conversations, ultimately in-licensing tibulizumab for our global rights within the Zura programs to advance within stages of autoimmune conditions. Yep, and how much work had Lilly done on this molecule before you out-licensed it? Absolutely. It's a great question. So they had already gone through, and just as a bit of a background, this was kind of a follow-on program to their anti-BAFF, their tabalumab program. And so there was a lot of evidence demonstrating the BAFF side of it had actually been functionally active and therapeutically beneficial. And then, obviously, the Taltz component of the molecule had been in the clinic for numerous years and had been approved. So for tibulizumab, they'd actually taken it through phase I studies that included early phase Is in rheumatoid arthritis and also in Sjögren's, demonstrating a therapeutic benefit, but also a really a pharmacodynamic engagement to allow us to understand also PK as well. So that enabled us, as we brought the molecule in-house, to go through and start thinking about what those indications were that would benefit the most- Yeah ... from patients who had elevated IL-17 and BAFF. Yeah, and I think that leads me to my next question, which is, you know, why SSc and HS as lead indications here? What gives you the most, you know, confidence that hitting both of those targets in these indications is going to drive some kind of differentiated efficacy? Absolutely. So first, before I even get to that, let me talk about the molecule just a tiny little bit- Sure ... because it is very nuanced. The traditional bispecific ends up with two variable regions attached to a single IgG. The way that this molecule is actually structured, and the best way to refer to it, is as a tetravalent dual antagonist, so one end of the molecule, which is the IgG directed against BAFF, and then the other end of the molecule actually has the single-chain variable region from Taltz that's attached to the Fc portion using a couple of linkers. This allows you to potentially use the molecule either as a single agent to target BAFF alone, or as a single agent to target IL-17A alone, and I'd be remiss if I didn't include the fact that the way in which we engage with IL-17A. I know there's a lot of conversations about 17A homodimers, and F, and et cetera. The way in which we bind to the IL-17A prevents the AA homodimer from forming and also prevents the AF heterodimer from forming. Mm-hmm. So it allows us to cover a majority of those inflammatory cascades. So that being said, again, we could actually have gone through and used it almost as a monotherapy, but what we specifically did within Zura was try to identify indications where the pathways of both IL-17 and BAFF were elevated within those individuals, so we could maximize the full potential of that molecule. And that ended up bringing us to systemic sclerosis and also hidradenitis suppurativa. Yeah, and I guess, you know, going into those indications specifically, can you talk about the evidence of impact of both separate pathways in each of those indications, and why you think combining will drive synergies? Absolutely. And so again, it's a great question. So one of the things that we wanted to do, and this has been core to a lot of the work that's happened within Zura, is that we've tried to leverage existing data to support this even further. And so IL-17 antagonism had previously been demonstrated, so Kyowa Kirin had advanced brodalumab, an IL-17 receptor antagonist, into the space. It was in a phase III program for systemic sclerosis, with a focus on scleroderma. And they demonstrated a positive benefit, perhaps the greatest improvement on the modified Rodnan skin score, an assessment of scleroderma. On the other side of it, we saw that Benlysta had actually been tested in an investigator-initiated trial, specifically for a systemic sclerosis and a focus on the interstitial lung disease, to the point where the evidence generated within that was granted an orphan drug designation within GSK. When we started to look at that data and we recognized the value of our compound, we recognized that there's still a significant unmet need. So, for example, the only approved therapeutics that are out there right now for systemic sclerosis exist for interstitial lung disease, not for the skin-associated version or any other components as well. And so that gave us an opportunity with our molecule and the evidence that was already there supporting this, to go through and think that we would get a broader effect or broader therapeutic benefit in the systemic sclerosis. That could include the skin-associated disease and also the pulmonary-associated disease. I guess what gives you confidence that, like, you're gonna see that these pathways are clearly, you know, orthogonal to one another, and you'll get some kind of a benefit on top of what's been observed across each monotherapy, you know, acted separately? Sure. So I think the benefit, again, comes down to the fact that the only approved therapeutics that are out there right now are for the interstitial lung disease. And so when you look at nintedanib and even Actemra, that are both approved in that space, their predominant benefit is pulmonary function, so they're looking at forced vital capacities. And so one of the things that we are enriching for and kind of measuring for within our clinical trials is an assessment not only of the skin score- Mm-hmm ... but also of the actual pulmonary function. And to that fact, we're actually gonna be using high-resolution imaging as well, to help us understand the impact of our particular therapeutic with tibulizumab on that pulmonary function. Yeah. Can you talk a little bit more about your phase II trial, some of the key design elements beyond enrichment there, and the timelines? Sure. So first and foremost, the timeline, we're still on task to kick off that clinical trial in the Q4 of this year. The idea is that it will be a randomized, placebo-controlled trial, looking at one dose of tibulizumab compared to a placebo, with an open label extension. And so as we move forward into this space, we're looking at the traditional enrollment criteria. We've actually engaged the help of a scientific advisory board member, Dinesh Khanna, to help guide us through that entire process, as we outline the rest of the clinical trial, and in the next couple of weeks, we'll actually be making more announcements related to the overall clinical trial design. Great. And then moving over to HS, you know, where do you see this mechanism broadly fitting in relative to, you know, the IL-17s and other programs in development? Another great question. So when you look at the emergence of the IL-17 landscape, specifically in hidradenitis, you recognize that there's a plateau. So a certain percentage of patients, whether it's with an IL-17A or even an IL-17A and F, ultimately, there's a plateau in the level of therapeutic benefit that they experience by just antagonizing the IL-17 pathways alone. When you look at the pre-existing literature, there's a demonstration and kind of evidence that supports the growing role of B cells, specifically within hidradenitis suppurativa. A couple of those papers have actually been generated by another one of our scientific advisory board members, Johann Gudjonsson. And within those papers, they demonstrate that the dominant B cell component within that emerging evidence is actually BAFF-driven. Mm. This includes neutrophils of those draining tunnels that are producing high amounts of BAFF and serving almost as a conduit to bring B cells into the site of inflammation within the skin. And so, you know, what we had looked at before was the obvious demonstration that targeting IL-17 is therapeutically beneficial. The area of B-cell targeting had been relatively unproven up until a couple of months ago, when a B-cell platform from Novartis had actually gone through, and they published the results from their remibrutinib study, their BTK inhibitor, demonstrating almost IL-17-like efficacy in a placebo-controlled trial. And so when you take again the combination of those two approaches, you know, you look at what tibulizumab can do. We can block the IL-17A and IL-17F for the most part, and obviously, we have the impact on the BAFF side of it as well. And so with a single therapeutic, we're able to go through and reduce the need for polypharmacology that would be required through the combination of IL-17s, plus some other therapeutic to get to the same level. Can you talk about your HS phase II timelines here? Absolutely. So we're looking, as of right now, to kick it off in the first half of next year from a clinical trial perspective, looking at a couple of doses in a randomized, placebo-controlled trial. And again, those details will be forthcoming as we identify the protocol a little bit further. And then, before we move on to your rest of your pipeline, I guess more broadly, you're hitting to, you know, well-validated anti-inflammatory targets, which, you know, as you hit those harder, they're also known to, you know, impact safety, infection risks, et cetera. Like, how has the prior data set kind of, you know, played out on safety? What are you thinking about in that context? Sure. So when you look back through a majority of the programs, and obviously, the benefit that we have is that we have publicly available data from Benlysta, from tabalumab, from the clinical trials, and then also from Taltz, that's been out there and used in hundreds of thousands of patients to leverage that existing database to inform our own safety understanding. And what we've learned from that entire process is that there's minimal safety risks. Obviously, we can't say that there's none, because there always is some level of a safety risk, but there's minimal safety risk, and it's well documented as what those are for systemic or for IL-17 antagonism and also for BAFF. And so we have a relatively good idea of being able to go through and move forward without any significant concerns at this point. ... Yep, makes sense. Maybe let's move on to, I'm not gonna try to pronounce this one, but your IL-7 receptor alpha program. So yeah, let's talk about the mechanism of action here, and what's the benefit really of blocking IL-7 signaling on top of just TSLP signaling? And how, I guess, broadly, how do you, do you think you could be differentiated relative to just TSLP-specific antibodies? Sure. So the molecule's name is lonzopnekhutug. It rolls right off the tongue. And so as you start to think through what the benefits are, this space is starting to grow with a number of players actually venturing into this, based on the increased targeting of not only the TSLP side of it, but also on the IL-7 side of it. And so very quickly, what happens and why you target IL-7 receptor alpha specifically is that IL-7 receptor alpha plays a central role, not only within the IL-7 signaling cascade, where the receptor itself forms a heterodimer with a gamma chain to control that signaling cascade, and T-cell activation and survival, and even some level of B-cell maturation. On the TSLP side of it, the IL-7 receptor alpha forms a heterodimer with TSLP receptor, and so that's actually what controls the TSLP signaling as well. So when you start to think about what the added advantage is for a number of these indications where TSLP has been predominantly tested, so obviously tezepelumab is approved for now within steroid-resistant asthma or severe asthma. There's additional trials that have been ongoing. It failed to meet its primary endpoint within chronic urticaria and also with atopic dermatitis. You know, some of the speculation that we have is that the added antagonism or disruption of T-cell activation will only be a perceived benefit on top of the disruption of the epithelial alarm and biology that plays a role within those allergic syndromes. And so, you know, the best way to think about lonzopnekhutug is as an opportunity of Tezspire plus T cell antagonism. And we've in fact gone through and not only that, but we've also demonstrated previously at the World Allergy Congress in 2023, that we are more potent at blocking TSLP than even tezepelumab, and that's due to the nature of our molecule and how we bind to the receptor that prevents the heterodimerization with either the TSLP receptor or with the common gamma chain. I guess to that point, you know, is there specific evidence in your view that, you know, going beyond tezepelumab, you know, it has to do with the IL-7 component as well, or more TSLP, hitting TSLP harder? So when you look at, for example, the lead indications that are out there right now, where the IL-7s are kind of exploring their efficacy, specifically, you're looking at ulcerative colitis, which is for the most part, a T-cell driven disorder. You're looking at atopic dermatitis, which is predominantly a Th2, but as you transition from an acute lesion to a chronic lesion, you also get a bit of Th1 and also Th17 in cases. And then for alopecia areata, which is relatively heterogeneous, and so you end up with a variety of inflammatory T-cell pathways targeting the hair follicle. There is a limitation in targeting TSLP alone, in that you're only going after, for the most part, the epithelial biology, where a perturbation of the epithelium triggers release of TSLP, and then downstream, you actually get the activation of the Th2 pathways. When you start to look at the IL-7, it has a much broader disruption pattern there. And so when you look at these diseases that are incredibly heterogeneous, and you look at the current efficacy of the therapeutics in those spaces, a broader effect is needed to get you an improvement on that therapeutic index, or, improvement, or therapeutic benefit, excuse me. And how does lonzopnekhutug compare to the Q32 bepemokibart molecule? And I guess, where do you feel like the evidence is strongest when you look at atopic derm and alopecia, you know, as we're thinking about these upcoming readouts later this year? It's a great question. So, there are now three different bodies of evidence that have gone through and have done a comparison between targeting CD127 or IL-7 receptor alpha alone, specifically with either ADX 914, the, Bepemokibart, even the OSE Immunotherapeutics molecule, and compared to Zura Bio's compound. And in all three of those, what we find is that there's relatively similar activity, in blocking the IL-7 compartment. But when it comes to the TSLP, aspect of this, what we have demonstrated, and also it's been reported as well by Q32, that we are, significantly more potent at blocking the TSLP activity. I guess when you think about alopecia and atopic derm, could you talk about kind of the level of evidence for TSLP slash IL-7 signaling there? And you talked about the failure of tezepelumab in atopic derm specifically. How does that shake out? Sure. So there's been emerging evidence as well. So there's other companies that have gone through and explored targeting atopic dermatitis with more potent anti-TSLP molecules, and they've also demonstrated a therapeutic benefit. So obviously, the addition of a T-cell blocker on top of that would be hypothesized to improve the overall benefit within those patients. Again, as you look at atopic dermatitis, it's not necessarily just believed to be a Th2-driven disease anymore. Yeah. You know, over the last, say, decade, we've started to understand this transition as you go from the acute lesions into the more chronic lesions that tend to be a bit more interferon or even potentially TNF driven, and to have a broader effect, rather than just targeting some of the early cytokines, Th2 cytokines of IL-4 and IL-13, even TSLP. So that's where the role of IL-7 comes in. Because you're disrupting T-cell proliferation and activation, you're going to have a broader effect on that T-cell compartment.... This is evidenced, you know, specifically for Zura Bio in the original type 1 diabetes trial that was run with lonzopnekhutug by Pfizer. They demonstrated a significant reduction in CD4 and CD8 T effector cells. And so as you carry this forward, those are the dominant cells driving atopic dermatitis, and even more so, those are the dominant cells driving alopecia areata, where the CD8 cells are actually targeting the hair follicle. And so you wanna see a reduction of those cells, which we believe will be better served by antagonizing the IL-7 component, as opposed to the TSLP. What does the path forward look like for l onzopnekhutug at this point? Sure. So we're a couple of months away from, you know, clear clinical readouts from the bepemokibart. We obviously have the readout that came from OSE earlier this year. So, the team, as of right now, is looking at those external catalysts as read-throughs for our molecule to help guide us as we think about our overarching strategy for clinical development. Additionally, beyond that, the team is also discussing additional indications, where we have the opportunity to lead the biology. And so, we'll be announcing some things over the next couple of months as we get those external catalysts coming forward as well. And then moving on to your final program, torudokimab, IL-33. Why is IL-33 such an exciting target? You know, what have we seen from the strategics in this space and in the later-stage development programs? Sure. First and foremost, when you look at torudokimab, compared to the existing landscape, what was previously demonstrated. And And again, this molecule we in-licensed from Eli Lilly. They had actually taken it through phase one and even in a phase two trial with atopic dermatitis. And so in their preclinical work, they had done comparisons to the etokimab, the AnaptysBio compound, and also the itepekimab, the Regeneron compound. And in a mast cell-driven assay, we've demonstrated superiority compared to both of those. And so we believe that we have a more potent compound to be able to take forward into this space. One of the things that we learned from the early-stage clinical trials with torudokimab is that there is a true targeting engagement. We saw a downregulation of IL-5, IL-13, and even some other molecules or biomarkers associated with pulmonary distress and epithelial damage. We presented that last year at the World Congress meeting as well, World Allergy Congress meeting. As we start to look at the external catalysts that are out there right now, there's a number of molecules that are currently still in development. Astegolimab, which is targeting the ST2 component of IL-33 signaling, and Itepekimab, that's targeting obviously IL-33, and those are both reading out, hopefully next year in COPD. One of the benefits of torudokimab, when you think about the dual biology of IL-33, is IL-33 signals through specifically two pathways. It signals through an ST2-dependent pathway and an ST2-independent pathway, and that independent pathway leads to the inflammation driving through RAGE and EGFR. That's been, you know, under discovery for the last couple of years as teams have gone through and tried to characterize that further. Because of the way in which we bind to IL-33, we prevent the signaling through both the ST2 dependent and independent pathways. So that gives us broad activity as we start to think about what epithelial disorders, where IL-33 is triggered, could we actually play a role in? Obviously, we're going to be monitoring some of the external spaces, as well as evaluating novel opportunities there as well. How does this binding consideration compare to the other molecules in development? Is there meaningful differences in the epitope of binding, like you suggested? Sure. So I think part of this is still under discussion and review, as we are all trying to understand how they engage specifically with the pockets themselves. But in theory, by disrupting the IL-33 itself, you would expect to have somewhat similar biology. The biggest difference that's going to come in is the potency within some of the assays and your kind of affinity and avidity of the compounds as you start to move those forward. And so I think we're gonna learn that through... You know, obviously, all of us can run preclinical studies, but the clinic is really the telling case for all of this. Yeah. There's a question from the audience asking about AZ's IL-33 compound, and any differences that you versus your compound. Sure. So Tozorakimab actually was the lead compound that had gone through from AZ to try and characterize both the ST2 dependent and independent pathways. And so obviously, we've been monitoring that space as well. We don't have anything specifically that allows us to compare back to that based on our preclinical studies, but we're closely monitoring their compound to see how it performs compared to what we expect and have observed with Torudokimab. So then, what does the path forward look like here? How important are these next set of strategic catalysts? Can you talk specifically about the timing there? Sure. So as of right now, when you look at the space for COPD, there's expected readouts for both Astegolimab and Itepekimab in the middle of 2025. Mm-hmm. It's a rather large undertaking to go after kind of COPD, and so we're closely monitoring that space. At the same timeframe, there's a number of disorders that we are evaluating internally to try and determine the level of conviction for IL-33 signaling and even the inflammatory pathways associated with those. So all of this is coming to some level of fruition in 2025 as we evaluate that for torudokimab specifically. Great. And then a final question here. Can you talk about current cash runway and embedded assumptions there with the path forward? Absolutely. So as of our last reporting, we have $188 million in cash. That takes us through the end of 2027. It allows us to actually execute on the systemic sclerosis phase II clinical trial, also on the phase II trial with hidradenitis suppurativa. Great. Mike, always a pleasure. Thanks for joining us. Not a problem. Thank you, guys.