Tech Equity Research team, and very pleased to introduce from Zura Bio, Sandeep Kulkarni, Chief Executive Officer. Sandeep, maybe set the stage for us for Zura. We are actually entering a really important point of time and period for the company with tibulizumab data coming up. You joined as CEO fairly recently. It seems like so much longer ago. Right. Maybe kind of give us the setup and why you joined Zura in this role at this point in time. Sure. That would be my pleasure. Josh, thank you for hosting me. It is really good to see you and be back here in New York City. You are right, we are entering a pivotal stretch for Zura, the most important in the company's relatively short history. The company, in a nutshell, kind of came together in 2022 around a few programs that we licensed from pharma. We are an autoimmune and inflammatory disease company. The thinking was, well, can we get molecules, can we get antibodies that are bifunctional or multi-specific in their nature and do multiple things, inhibit multiple pathways? And that's the kind of thing that I think we hear echoed from a lot of folks, is seeing the efficacy ceiling seen with single pathway modulators and recognizing that we may need to do more than just hit one pathway, however hard, to really get that degree of benefit. The three programs that we brought in all are multifunctional in nature. They all came with clinical data sets from the pharma companies that we licensed them from. The lead program is tibulizumab, which is a bispecific antibody we licensed from Eli Lilly back in 2023. We, and they describe it as a four-headed hammer in that it's tetravalent, it hits two targets, IL-17 as well as BAFF, both of which are highly characterized, highly validated targets across a number of indications. And we can uniquely modulate both those pathways with a single antibody. As we both kind of noted, we are entering a really critical, important stretch for the company where we'll have our first two data readouts coming over the next six-ish months. The first one being our hidradenitis suppurativa study reading out in Q4 of this year, and then followed by a phase II readout in systemic sclerosis, both of which we think are high value indications with high unmet need that a drug like ours, given its bifunctional nature, could be uniquely well suited to address. As I was considering my opportunities post my previous company, I was just really excited by what was happening at Zura, where a lot of things we had said, I think we were maybe a little bit ahead of the curve in terms of being excited about bispecifics, excited about multi-specific drugs for autoimmune disease. We're starting to bear out the data across different mechanisms, different indications, with suggesting that this really has some real legs. The company was getting close to a couple of readouts. There were other indications that we could potentially pursue with tibulizumab. We have other assets here, and so it truly was too good of an opportunity to pass up as we enter this critical stretch for the company. Because you had recently said to me you joined for more than just a phase II readout. Yeah. I guess that's kind of what you're alluding to, the rest of the portfolio or the vision. Yeah, I think that's right. If all we had was a binary readout in HS, I still would've been really excited about it given the evidence supporting- Yep the role of BAFF as well as IL-17 in HS, and the fact that we are doing something that is different. The fact that we already had two high-quality shots on goal with tibulizumab, we just announced a third indication, polymyalgia rheumatica, that will start later on this year with tibulizumab, another, we think high quality, high probability shot on goal. Even beyond it, the optionality from the pipeline, it was again, there's a lot of different directions to go, which I and we as a team are excited to pursue. All right. Excellent. We're going to spend a lot of time on tibulizumab, but I think the context is important here because the three assets that you in-licensed from pharma, we actually now have the other two that are being validated. Yep. Right? Suggesting that there is a very keen eye for unmet need in the immunology space. Maybe talk a little bit about the IL-7 receptor- Sure external validation, IL-33, plans you might have for those programs, but more importantly, talking to the keen eye- Yep right, to have those two now validated and what it might mean for tibulizumab. Yep. So starting with crebankitug, our IL-7 receptor antibody we licensed from Pfizer back in 2022. It binds the IL-7 receptor alpha chain, which importantly is shared between the IL-7 receptor complex as well as the TSLP receptor complex, and so by virtue of a drug like crebankitug, we potentially could inhibit both of these pathways, speaking to the idea of finding drugs that can do more than just one thing, inhibit multiple pathways at the same time. When we first started, there was some degree of genetic work supporting IL-7 receptor across a number of indications. In a cash-strapped environment, we had to prioritize tibulizumab, but we were always excited about crebankitug and the potential it had across indications. One of the indications that we initially had proposed to pursue with IL-7 receptor was alopecia areata, where, as you alluded to, there's now recent clinical validation for IL-7 receptor blockade in that disorder, where we think this is an important advance in a field where all the drugs approved to date have been JAK inhibitors. We think there's very strong desire from docs we speak with in the field for a non-JAK way of modulating a disease like alopecia, not to mention other more TH1 constellation disorders where IL-7 receptor could be an important advance. In the case of IL-33, this is an alarmin where there's been very strong signals seen across respiratory indications and recently some data from AstraZeneca suggesting what we think is a strong profile in COPD with a couple trials showing good reductions in exacerbation rates. We're lucky to have these programs in our pipeline. We do think they present some interesting optionality for us. We've tried to be thoughtful about how we pursue indications, to pursue ones where there's a unique, differentiated development path that we can pursue. We continue to work through ways we might be able to advance those programs. Could be us internally, could be with partners. As I think you rightly point out, there's growing interest even relative to where we were a few years ago, for each of those programs. Got it. I think also really does reflect well on the company's I&I acumen to have already pulled out two solid indications even before they were clinically validated. Yeah. I appreciate you saying that. I think when we first get programs, we wonder, are we crazy thinking this could work in these indications? I think HS is a great example where I think we were ahead of the curve here saying IL-17 is good, but there are B cells that are present in this disease, in the lesions of patients with HS. Can we use something like tibulizumab to break through the efficacy ceiling? I think the data that have come out since then are lining up in support of that hypothesis. A common question that comes up, Zura is increasingly a topic of conversation as we're getting close to really important data in a therapeutic category- Yeah that many investors are very interested in. One question that comes up is, as we think about the profile of tibulizumab, having IL-17 activity but not having IL-17F activity, what you might give up there versus what you might gain by having a BAFF component- Yep versus what you might be giving up by having BAFF but not full B-cell depleter. Yep. Trying to figure out some kind of math that gets us to an answer. I'm guessing there is no math that gets us to an answer, but conceptually- Sure Maybe you can talk a little bit about those trade-offs and how you think tibulizumab is positioned now in HS. Yeah. I am happy to do so. Maybe I will start off by noting that we love HS as indication. We are not an HS-only company here, and so we appreciate the investors that are tuning in. But I encourage everyone to look deeper in the pipeline, see the other things that we are doing that we are also very excited about. In terms of HS and FF versus AA, I will try to simplify this out as best I can. The truth is, until we have clinical data, it is hard to make really definitive claims. But I think there were some inklings of data that I will tell you what we know and how we interpret it. So there is strong validation that IL-17 is involved in HS. It is by far the most studied, most validated mechanism across a couple different drugs approved, other drugs have shown positive signals as well. I think the question has been, well, which species of IL-17 is truly driving activity? Is it the IL-17A? Is it AF? Is it the heterodimer AF in between? And there were various theories on it. There is not really great preclinical ways to parsing out the relative roles of each of those pathways. However, looking at the clinical data, I think they are by and large in the same category. I think the jury is still out on whether FF blockade specifically does drive incremental benefit, though I think where it is more clear is that it does drive some differential safety observations, including higher rates of candidiasis as well as skin eruptions that have been commonly reported for IL-17AF combined blockade. I think, and again, as noted, the kind of FCUC with IL-17 inhibitors kind of gets you all within the same category, which is good, but certainly not great. Certainly not like the psoriasis-like response rates we see with IL-23 inhibitors or even IL-17 inhibitors. So HS is a little bit of a different beast, and I think most folks in the field recognize the challenge there. I think that begs the question of what is happening in HS that makes it different? If it is not purely IL-17 driven, what other pathways are involved here? We think making this a really great example to test a bispecific. The role of B cells has been described in that they are present virtually all HS lesions. If you take blood samples from HS patients, you will see very high levels of immunoglobulin present, again suggesting that there is something that B cells may be doing contributing here. Now we have some clinical validation for multiple B cell-directed therapies, all showing concordant benefit on traditional metrics of HS, all suggesting a role for B cells here that has not been fully explored. BAFF specifically is elevated in HS lesions. It tracks with disease severity, having high levels of BAFF in your blood predicts non-response to other standard of care therapies, things like TNF inhibitors. All suggesting that it is a story that kind of triangulates, suggesting that they play a role here, which we can put into a single molecule. The question you ask of, well, what are we giving up by not hitting AA versus what we are going to get by hitting BAFF? We will have to get the data for it, but if all we had was a B cell-directed therapy for HS, we think that already gets us in the same categories where some of the other therapies are, and we are putting these together in a non-redundant way. I would say stay tuned to it. I guess what is interesting about that B cell validating external data set is they are not B cell depleters. Right. That would suggest you do not necessarily need to deplete the B cells. Yes To get an anti-B cell effect like you're getting with BAFF. Yeah. I think that's right. I mean, to be clear, BAFF inhibition will get reductions in B-cell counts, but more like in the 40%-60% reductions in B-cell counts versus a true B-cell depleter would get you 100%, 99% kind of reductions in B-cell counts here. So it does appear whether you have a B-cell depleting effect or something more like a BTK inhibitor, you still see concordant benefit that directionally trends the same direction. So no matter how you modulate the B-cells, it appears that can drive some degree of activity. To your point, almost a single-minded focus on the TibuSHIELD data coming up. Yeah Even though there is a lot more happening at Zura. Why don't we drill into that trial? Sure. Give us a quick overview of the design and some of the endpoint considerations and primary endpoint selection that you made and why. Sure. Yeah. Our pleasure. TibuSHIELD is a 3-arm study. We initially had planned to enroll 180 patients in the study in January before I joined as CEO full time. We had upsized the trial to 225. We ended up over-enrolling the trial, with enrollment completing with 247 participants in the study. Again, folks are randomized to one of three arms, two active arms against placebo. The study drug is given at week zero, week two, week four, and then every four weeks beyond that, primary endpoint at week 16. After the primary efficacy period, participants are able to enter an open label period where they can get an additional four injections of study drug. The completion of the study at week 32. By and large, this trial looks similar to other proof of concept trials in HS. The inclusion, exclusion criteria are largely modeled on other successful phase II trials here, and this was important to us to make sure we can deliver a data set that is interpretable by the field, and comparable relative to what others have done here. The primary endpoint for the trial formally is the AN count. In HS, it is characterized by different types of lesions on the skin, including abscesses and nodules, which are added together, which form the AN count. We are looking for change from baseline in that AN count as the primary endpoint for the study. The regulatory agencies have preferred a responder analysis, using what is called the HiSCR, which effectively is the same. Using the AN count, it counts the percent reduction in the AN count to determine whether you became a responder or not, depending on whether you met a threshold of, let us say, 50% or 75% reduction. Historically, both HiSCR 50, meaning a 50% reduction in the HiSCR in the AN count has been the preferred endpoint. Lately, there has been a move to push to a higher, more stringent threshold of HiSCR 75. We think that is important. We hear that from the docs in the field of wanting drugs that work deeper, have more response that they can drive deeper response rates. We have powered the trial formally for HiSCR 75, recognizing the importance of that for regulators here. We're tracking other things in the trial such as B-cell counts, immunoglobulin levels, things that will help us give some signals about what the relative role of BAFF versus IL-17 may be, even though the trial is not formally designed to test that concept. Since the trial is so much bigger than initially planned, is there a potential to turn this into a pivotal trial? If so, would it make any sense to approach the FDA and ask for the HiSCR 75 to be made the primary endpoint now? We've designed the trial rigorously. It is intended to be an adequate and well-controlled clinical study. The question of whether it can count as a pivotal or not is more a discussion with the regulators. Our base case has always been that we would need to do two pivotal studies after this in line with other precedent drug development programs in HS. It, of course, depends on the data. If the data are strong, we can, of course, have that discussion with the agency, but base case would be that we would need to do two studies. We're no worse off for having AN count as the primary endpoint. Given that we are powered for HiSCR 75 and the signal is robust on HiSCR 75, of course, we'll take that seriously. Okay, got it. I believe AN count improvement does generally correlate with HiSCR. Absolutely. What is the advantage then of having that as the primary? Right. The change from baseline AN count is a continuous variable so that continuous variables tend to have more power relative to categorical endpoints where someone may just miss the threshold or may just cross the threshold, and that may just introduce additional noise into your endpoint versus a continuous variable avoids some of that. We are doing what is precedent that has been set by other programs. Povorcitinib, as an example, used AN count as the primary endpoint for its phase II trial. Again, recognizing that HiSCR 75/50 will be captured in our study, and we will report those data, of course, and those likely will be the primary endpoint for a future study. But essentially, it just gives us greater power. Got it. Can patients who had been exposed to an IL-17 inhibitor be enrolled in this trial? I think that it is an important point. We have excluded those from our phase II trial in large part because this is the first time that tibulizumab is being tested in HS. We wanted to run a clean experiment in a population that truly is analogous to other populations, similar to phase II trials for other IL-17 inhibitors. We excluded them from the study. However, this is a group that we are absolutely interested in testing in later development, potentially in parallel or as part of the phase III studies looking at IL-17 experienced patients. If we look at psoriasis as an example, there is precedent that if you respond and lose response to one IL-17 inhibitor, you can still respond to another IL-17 inhibitor as well. Similar pattern in RA with the TNF inhibitors, for example. We believe that we potentially should have activity here, especially with the BAFF component here that may drive a different response profile relative to just another IL-17. The most common question I get by far is what does the data need to show? Yeah. I guess first of all, what are you hoping to show, and what do you think the minimum that you need to show to continue to advance the program would be? Absolutely. Yeah, I'm glad you framed it that way, where we just spend a lot of time talking with investors about what is the minimum efficacious scenario. But we go into this looking at the fact that we have a very good IL-17 inhibitor, using the CDRs that come from Taltz or ixekizumab, Lilly's IL-17 inhibitor, which is a very good IL-17, has shown what we think is highly compelling data that exceeds what's been seen with some other IL-17 inhibitors already. Just by virtue of that alone, we believe that we have a good IL-17 on one side. If BAFF adds anything, we think we really have a shot at being the best drug, or at least among the best drugs for HS, if we're right in this idea of two pathways, non-overlapping mechanisms in a complex disorder. But in terms of thinking through what is the minimum bar that we're looking for, we think a 20 percentage point delta on HiSCR 75 is a reasonable place to start. That would put us, we think, at the upper end of what's been seen across phase II and phase III studies for other novel agents in HS. I think that's part of what we're hoping to show. I'd also recognize, though, that I think in light of the unmet need here, maybe the subpar efficacy seen with approved therapies for HS, we think there is not a sole reliance on just a single number here, but there's a little bit more of a totality of data here, looking at absolute responses, potentially on other endpoints, HiSCR 90, HiSCR 50 as well, that we think are important kind of take all into account. But I think HiSCR delta of 20 percentage points on HiSCR 75 relative to placebo would be a good place to start. There seems to be a fair amount of noise in HS studies, placebo response rates, signals that may be a little hard to reproduce from one study to the next. Is there any way to minimize the noise in these trials? If so, how? Yeah, I think it's a challenge not just in HS, but across dermatologic indications where placebo responses can be a little bit all over the place. I think we all should go into a derm study and certainly an HS study recognizing that placebo responses are here to stay, and we need to think through how to design trials and execute on the trials to minimize that as best we can. For us, that started with picking a CRO that's experienced in doing HS studies, picking investigators who have done HS trials before, given that there's no objective way to measure the abscesses nodules. It really is by palpating them. We've invested in training our investigators and then retraining our investigators midstream in the study, and we've also invested in a blinded medical monitor to review data as it comes in from the study to essentially track for anything that looks unusual that may warrant a query to the site. I guess the final piece is we've over-enrolled the trial here. As noted before, we upsized it from initial 180 to landing at 247, really make sure we have enough patients here to weather any upward creep in the placebo rate. Yeah. I think what is very interesting is that there's such anchoring around the what do you need to show question. Yeah Not a lot of commentary at this point around what could you show, because theoretically,- Yeah it could really differentiate versus all other HS data sets because they're the first one exploring two mechanisms in one. Right. But obviously we don't know until we get there. Yeah, outside the conversation, we're talking about how biotech is hard. We all recognize that it's very hard to predict anything with absolute certainty in biotech. But yeah, I agree with you that we go into this thinking there's a legit chance that this could be the best drug in HS. We of course have to get the data, and we're not going to set the expectation there necessarily, but there's certainly that possibility. There's a non-zero chance that is the case. Yeah. No, because I get so immersed in these what does it need to show conversations. Yeah That you have to step back and acknowledge it may not be a subtle signal. It may be a very dramatic one. It could be subtle. It could be dramatic. One question again that comes up is it's a bispecific, the risk of autoantibodies, and, sorry, antidrug antibodies. Yeah I should say, and what do we know about tibulizumab and that particular consideration? Yes, so an important question, given some of the chatter in the field about all this exotic engineering leading to high ADA rates and immunogenicity seen with bispecifics. We know from the team at Lilly that a lot of effort was taken to minimize immunogenicity as best they could. Thus far in the clinical experience across phase I and phase I-B, the rate of immunogenicity has been low. What we've said is sub 5% of patients with treatment-emergent ADAs in the phase I-B experience. So relatively low thus far without any apparent impact on PK for the drug. That compares favorably with some of the other competitors that aren't even bispecific, things like bimekizumab, for example, has a relatively high rate of ADAs. 60% of patients in their HS studies had ADAs, of which 60% was deemed to be neutralizing. This is directly from their label here, so it hasn't compromised Bimzelx from being a good and important medicine for any number of indications. But I think it's important to put ADAs in context, and thus far, luckily, it's been relatively low. What's so interesting is we could have this exact same conversation, but instead of HS, talking about scleroderma- Yes and the potential with the same reason to have a very outstanding data set by combining two mechanisms. I guess, first of all, maybe just review the design of the scleroderma clinical program and the timelines for that. Yep We'll go a level deeper after that. Sure. This is the TibuSURE trial, where we're looking at tibulizumab, 300 milligrams, given that same dosing fashion week zero, week two, week four, then every four weeks beyond that, versus placebo. We had initially planned to enroll 80 subjects. We ended up enrolling 91 in total. We completed enrollment in July, and we're on track for data first half of next year. We're excited for that indication as well, where we are testing something different than what others have done here. The primary endpoint for the trial is the modified Rodnan skin score. Like HS, the endpoint's unfortunately not objective, involves pinching the skin, feeling the toughness of it for the modified Rodnan. It's sort of been the primary endpoint that folks have used for proof concept phase II trials. For us, we wanted to incorporate an objective measure as well, and so we are doing CT scans for all subjects in the study at baseline, at week 24, and then at the end of the overall study here. CT is objective, and so there are a few protocols and ways to essentially measure the degree of lung fibrosis as well as the interstitial lung disease that unfortunately occurs in patients who have scleroderma or systemic sclerosis. So we are tracking that with CT as well, to hopefully get the most robust data set here that we can look through and decide how we take that forward beyond phase II. How correlated do you think HS is with scleroderma? Part of that question is, if you see an excellent result in HS, certainly your hope and encouragement and enthusiasm for- Yeah scleroderma would also be increased. Honestly, hand to heart, I don't think there's much read-through between the two studies. These are very distinct. They're distinct indications. The relative role of IL-17 and BAFF could very well and likely is different between the two of them. We don't view there to be a lot of read-through from one to the other. Of course, if there's a pharmacokinetic or dynamic failure for the drug, that would be important and be problematic. But the biology is distinct enough here that we don't think there's a lot of read-through. That's in part how we pick our indications, is to really take high-quality, independent, uncorrelated shots on goal. PMR, I think, is something that's similar in that vein as well. Sure, I'd love to tell you that if our HS trial blows the lights out, does that mean SSc is going to work? Again, I think it's hard to draw that connection here, but these are independent high-quality shots on goal that we're taking. And then maybe the last question in adding PMR as the next program and indication, I am inferring that is also not correlated to HS or scleroderma, but why advance that indication as opposed to choosing between crebankitug or torudokimab for IL-7R or IL-33, instead of now tripling down on- Yeah tibulizumab? So, it is a good question. It is also a good question to have that to be in a situation where we have multiple things we can choose from. I would not necessarily view this as either/or. It really is more of a question of sequencing. Given the investment we have already done in tibulizumab, some of the emerging data sets here for PMR, including for IL-17 as well as for B-cell-directed approaches, again, it was too good to pass up and was something that we could get off the ground very quickly. In the case of resourcing the other programs, again, our development decisions for tibulizumab do not necessarily read through to what we do with the other programs as well. We are exploring ways that we might take those forward, again, either ourselves or with partners here. And when do you think we might get updates on those programs and strategy? Yeah. We are not getting any younger, so we try to move quickly. We have a lot on our plate right now with tibulizumab, of course, with two trials reading out in the near to medium term, another trial that will get going by end of year. I will say the work that we are doing on crebankitug and IL-33 is high. There is interest internally to quickly define those paths and move forward on them. Excellent. We're out of time. Sandeep, terrific discussion. Thank you, Josh. Thank you. Thank you so much. It's always good to be here. Looking forward to the data updates around the corner. Yes, absolutely. f exciting. Thank you. Thanks, everyone.