Good afternoon, everyone. Thanks for joining us here on day two of the Leerink Partners Global Healthcare Conference. My name's Tom Smith. I'm one of the senior biotech analysts here at Leerink, and it's my pleasure to welcome our next company to the stage, Zura Bio, and happy to be joined up here by our Co-Founder and CEO, Sandeep Kulkarni. Sandeep, thanks for joining us. Thank you to you and Leerink for hosting us. I think this is the third company that we've worked on together, so I'm eager to be back in the seat. Yes. Let's start there, right? Like, for those in the audience who may be a little bit less familiar with Zura, maybe give a little bit of background, and then you just recently joined in the CEO role. Obviously you're a Co-founder. Yeah. Quite familiar with the company, obviously, like very involved in the company, but like why, you know, why come back into the CEO role so quickly after Tourmaline? Yeah. It's my pleasure again, thank you for hosting us here during biotech spring break as we're now calling it. I helped co-found Zura back in 2022, right at the same time that we were also my team was co-founding Tourmaline Bio, which you know. I stayed on as CEO for Tourmaline, but I was a board member for Zura since day one. You know, the company's made a ton of progress where we have three programs in the pipeline. Tibulizumab, we'll talk more about, is a bispecific that really has a unique first in class potential here and a very exciting you know set of indications too to pursue. That is our lead program where we're focused right now. We've been in execution mode for the last few years, but now we are transitioning to a year of data. 2026 and 2027, over the course of the next 18 months, we'll have two important phase II readouts and two very different indications, each of which presents a massive opportunity for us to be going after. When my previous company, Tourmaline, was being acquired, I would've loved to take more time off. The truth is that this was too compelling to pass up, where internally, you know, our faith in the program, our confidence in the program has only increased, plus the number of external developments that I think further lends credibility and validation to the ideas that we're pursuing with tibulizumab in our indication. in short, it was just a big year. This is a big year for the company. I'm eager to be a bigger part of it. Awesome. Great. Let's dive into Tibu. Yeah. Tibulizumab. As a bispecific, you're combining IL-17A blockade with BAFF inhibition. High level, what was the hypothesis here for going into hidradenitis suppurativa? Yeah. which is your phase II readout coming later this year. In Q4, tibulizumab, as you noted, is a bispecific antibody that binds to two very important targets, IL-17 and BAFF. All right. We got this program from Lilly, and one of the things that makes this molecule special is that it is a combination of two well-characterized antibodies in Lilly's hands. On the BAFF side, it uses essentially the backbone and binding regions for tabalumab, a phase III BAFF antibody they'd taken through phase III in lupus. Then on the other side, grafted on are the single-chain Fvs for ixekizumab or Taltz, which is a very successful IL-17 antibody approved for a number of indications, including psoriasis, and sells quite well. It was a unique opportunity for us to get an antibody where we can get the benefit of two highly validated, highly characterized portions of the antibody put into a single molecule. There's been a real explosion of interest in using bispecifics as a means of breaking through the efficacy ceilings that have been seen with single pathway modulators. When we looked at this program, we were excited about the potential here to, you know, not just do the same thing twice, but to knock on two very different doors, go after two kind of sets of biology, all with the same compound. On the IL-17 side, as you pointed out, there is validation for IL-17. HS is our lead indication here. What makes ixekizumab and tibulizumab, insofar as it binds IL-17, unique is that it's not just IL-17A. We can also bind to the IL-17AF heterodimer, which has shown validation and can do that with high potency. It may explain why in other indications, Ixekizumab, the parent for our antibody, has shown very good data relative to other pure IL-17A antibodies alone. All right. Now, HS is a complex autoimmune disorder where there are different components at play. There's T- cells, B- cells, neutrophils. Our thesis in going to HS was in an indication that's this heterogeneous, where single pathway modulators have shown limited efficacy, the way to break through that may be to engage multiple pathways at the same time. Now, what makes Tibu exciting from our point of view is the degree of validation for both sides of the antibody, for both IL-17 as well as the BAFF component here. BAFF being a proxy in some ways for B cell activation. BAFF is elevated in HS lesions. B- cells are present in HS lesions. But there's been emerging datasets now that further validate BAFF for HS specifically. As we think about our phase two program, we have a shot here of really bringing together the best of both worlds and engaging two pathways, each of which have been validated in this disease to hopefully like be a best in disease treatment for, again, what is a complex autoimmune disease. Yep. Wanna dive into kinda both of those doors that we're knocking on. On the IL-17 side, very validated. Cosentyx approved. I think investors, and this is, like, I would love to get your view on this. Investors, I think, broadly view bimekizumab, which is IL-17AF, as, like, the most effective option in HS. One question that we get from folks is, like, do we potentially lose something on the IL-17 side by not having F? Like, how do you think about that? Let me take that a couple ways. Based on the data we've seen so far and in Lilly's hands in phase I and phase I-B, we get very good target engagement, upwards of 98% for both IL-17 and BAFF, based on the phase I-B data they had generated. We don't think we're leaving any efficacy on the table here with our tibulizumab by binding to IL-17 very efficiently, as demonstrated in the earlier studies. Now, I think this raises a different, you know, question about how do you get to a step change better efficacy relative to existing treatments. We agree the data for Bimekizumab is strong and maybe better than Secukinumab. However, we're not talking about an order of magnitude better or step change better. Our view is to kinda get to that next level, you probably need something that does more than just hit IL-17 alone a little bit harder or a little bit differently. You're starting to maximize out what you get, you know, from that pathway, for modulating that one pathway alone. This is where bringing that additional mechanism by via BAFF, and its impact on B-cells could potentially help break through that. We've seen that in other autoimmune, autoinflammatory disorders where bispecifics are starting to prove out the promise that going after two pathways at the same time may again sort of avoid some limitations or surpass limitations of previous monospecific therapies. We're trying to bring that to HS, where we're the only company that we're aware of going after these two very different pathways in the same molecule. It is a first-in-class opportunity for us. Yep. That makes a lot of sense to me. Just on the other door, the BAFF door. Yeah. Like how much validation we've seen the ianalumab experience, but in like a very limited fashion. Yep posted on ClinicalTrials.gov, kinda like very truncated data set. How much validation do we feel like there is in BAFF B cell modulation in HS? Yeah. The idea that B- cells are present in HS, in HS lesions goes back where there's very strong data looking at biopsies, showing that whether you look at draining tunnels, nodules, abscesses, kind of the characteristic lesions you see in hidradenitis suppurativa, you see B- cells. In fact, you also see things called tertiary lymphoid structures, which are aggregates of different cell types, but in part, in large part B- cells, which may drive crosstalk between different immune cell components, within the tertiary lymphoid structures. There's no kind of doubt about that. The question has been, what is the functional relevance of those B- cells? Maybe more important from a therapeutic point of view is what is the functional benefit you'd get from modulating the activity of those B-cells? When we first got going with getting an HS trial started, the thinking was, we can rely on, like IL-17 here, given its validation to drive a high degree of, you know, activity within HS, and then take a bet on, what does the B-cell component, you know, do here? Now, over the course of the last year, there have been multiple agents and different mechanisms all within the B-cell-directed family that have shown positive signals of activity. You noted the Novartis platform study that read out where they announced results last year. They published data on ClinicalTrials.gov, where three different mechanisms that are all related to B-cell functioning, BTK, CD40, and the BAFF receptor antibody, all showed positive signals of activity. Any one of those mechanisms may not necessarily tell the whole story, but the concordance of effect across those three mechanisms, we think points to, you know, a clear therapeutic rationale for targeting therapy directed at B-cells. We have to run the trial to kind of prove the point, but we're not asking the B cell inhibiting effect, the BAFF effect to do the heavy lifting. We have the IL-17 for that, and we're asking BAFF to bring something to the table, and the evidence would suggest that BAFF and B cell inhibition does drive some degree of activity in this or benefit in this patient population. Yep. Let's talk about the clinical side of this and, you know, the Phase TibuSHIELD study that is underway. Talk about, you know, patient population that you're targeting, any unique aspects that you would highlight to the TibuSHIELD design. Yeah. You also recently announced that you're gonna basically expand enrollment, give it a little bit more power. Sounds like it is largely on the basis of it's enrolling quite well and the patient demand is there. Talk about some of the kinda design aspects to it that give you confidence that you're gonna be able to tease out that signal. Sure. The TibuSHIELD study is a phase II trial. By and large, we've designed it similar to other phase II trials in HS. We're not trying to recreate the wheel here in terms of trial design. The study is 225 patients in total randomized to one of three arms, two active drug arms versus placebo. We're testing 300 milligrams, 150 milligrams, again, versus placebo. Drug is given at week zero, week two, then week four, and then Q4 weeks after that. As noted, primary endpoint is at week 16 for the study, and then patients are eligible to roll into an open-label extension afterwards. In terms of inclusion and exclusion criteria, again, these are by and large similar to other studies. We are looking to enroll folks who have moderate to severe HS, defined as early stage two or three. We do cap the percent of patients who can have early stage three to avoid any concern that folks whose disease may be so advanced that they're unlikely to respond to any treatment at that point. We do allow folks to have prior biologic exposure, namely adalimumab. We do, again, cap that at 30% to avoid just to really have a clean population to demonstrate the effect of the drug. This is the first time that tibulizumab has been tested in HS, so it is a proof of concept study intended to serve that purpose. The primary endpoint for the trial is change from baseline in AN count, AN being the abscesses and inflammatory nodules. However, the regulatory endpoint is the HiSCR, either HiSCR50 or HiSCR75. We've powered the trial for HiSCR75 delta versus placebo of 20%-25%, which we think reflects a reasonable approximation of what is the clinically meaningful effect, here, again, in maladies where the treatment options are suboptimal, and there's a lot of folks who don't respond well. In the trial, we did upsize the study from 180 up to 225. That was driven, honestly not like necessarily because the trial was going really quickly. It was slightly ahead of schedule, but this is where we wanna be mindful of what we see in the external environment. We wanna make sure we can maintain robust powering, even if the placebo rate trickles up a little bit based on, you know, recent experience that we've seen. Maybe more importantly, it's also to really ensure that we have a robust data set to draw the conclusions to be able to design the phase III trial as robustly as possible. For a relatively small hit in terms of timing, it was the right decision to upsize the trial. Again, we have more data points here. We can design the best trial on the back of this phase II. That makes sense. You touched on placebo response that we've seen in some readouts, slightly elevated placebo responses that have somewhat dramatically impacted potentially interpretation of those results. Yeah. Like, what are the steps that we've taken in TibuSHIELD to help mitigate placebo response? I think you guys have taken some pretty novel approaches with respect to site selection and other things. Yeah. Just elaborate on how we're managing for placebo response. So before we get into details of the trial, like I'll just say like when we look at a drug like ours with a very good IL-17 on one side and the belief that BAFF should add something on the other side, we're shooting for a best in disease profile here. We think with a drug like ours, going after two validated pathways, we have that, you know, kind of potential. All right. If we are shooting for that, the placebo, you know, outperforming by a couple percentage points shouldn't matter that much. Now, that said, we recognize that placebo responses have been present across every HS study, and maybe some suggestions from a few kind of notable recent outliers that those placebo response rates have trickled up. In terms of like managing that, like first of all, we've over-enrolled the trial, so that gives us an additional, call it 2-3 point delta in terms of benefit that we can still see even if placebo trickles up by that much and maintain our powering for the, you know, for the study. In terms of clinical trial execution, we've tried to be very careful in how we design the trial and how we execute it as well. That started with picking a CRO that is a derm-specific CRO that only does dermatology studies and has done HS trials before. Beyond that, we've only picked sites and investigators within those sites who have done HS trials before. There's unfortunately no centralized way to measure AN counts, and so we rely upon the expertise of investigators to accurately and precisely measure AN counts at each visit. Before the study started, we invested in training our investigators on how to measure AN counts or for all of them as a refresher on what they've done before. To do a mid-cycle retraining again to ensure that everyone's up to speed and everyone's doing things in a way that is consistent. We've implemented that across all of our sites with all of our investigators. Got it. You, you've alluded to this 20%-25% range as like clinically meaningful. I guess just, maybe more specifically, like your expectations for this study and I guess, you know, if, and we talked about placebo response. Yeah probably not dramatically altering like your interpretation of the signal. Maybe talk about other scenarios where like let's say that you landed at like a high teens, like an 18-19, does that mean we don't see this as competitive or there are alternatives paths forward? Like how do we think about that? With that, I'll start noting that it's our hope and belief that with a drug that can engage two pathways, both which are validated, we can be on the upper end of, you know, that range or potentially exceed it. That is our hope. Right. Now, if we end up on the lower end, I mean, I think this is where if we take a step back and look at the HS indication, this is an area where the unmet need here is almost certainly bigger than any company or current groups give it credit for. Most estimates are roughly 8% of a population has like HS, based on claims data, other epidemiologic studies. We're talking about really quite large indication where there has not been a lot proven. I think that pharma and investors certainly kind of acknowledge that this is a big indication where none of the options are great thus far. In a world that is almost certainly gonna evolve more like other autoimmune disorders where folks try one drug then cycle to something else when that stops working, HS is gonna be a great example of that. We have a few drugs approved, a couple different classes thus far. As more therapeutics come out, I think it'll create greater segmentation of the overall market. Even if we're in a world where we are below that 20%-25% range, we think there's an important place where a drug like this can play. Now, we are not necessarily another IL-17A or IL-17AF antibody alone. We are a first-in-class drug binding to these two different pathways. By virtue of bringing the B cell targeting component, we think that may work differently than other drugs here. It can still find a way even if we're below that range here. If we look overall, like in the market, we think that's what the market is telling us, that being a new drug, even if you're similar to other drugs, is still like worth something important. If we can bring something to market that really does work differently, all the better. Now, the role of B-cells, we think could be particularly pronounced in certain types of lesions, namely draining tunnels, where B-cells and those tertiary lymphoid structures I mentioned before tend to be highly present. We will track that in the phase II. This is a proof of concept study, but again, goal is to get enough data here that we can hypothesize that we can refine or test, refine, and then incorporate into our phase III plans. That makes sense. Those secondary analyses are also going to be really important. This could manifest in IHS4, 100- Potentially, yeah. response rates. Things like that. There are other ways to look at this data set. It shouldn't probably just be myopically focused on HiSCR75, I would argue. Yeah. I mean, we know HiSCR75 is what the agency prefers, or HiSCR50 or HiSCR75 is what the agency prefers. But I think most docs will tell you, most patients will tell you that the disease is quite heterogeneous, and HiSCR may not capture all of the symptomatology that's problematic. We hear this from patients and docs that the smell, like the tunnels may actually be more problematic than just the nodules and abscesses alone. It is a complex disorder where a treatment like ours has a shot at doing something very different than other drugs here. Yep. A chance to differentiate on other things besides perhaps HiSCR. Yeah. Yeah. That's right. Cool. Let's shift gears and talk about systemic sclerosis. Maybe like we'll start in kind of a similar place, talk about biologically, like what drove you to this phase II SSc study that's gonna read out first half of next year? Yeah, certainly. SSc, systemic sclerosis, has certain commonalities, but then important differences relative to how we think about HS. Commonalities, first and foremost being it is a complex immune disorder, and the standard of care here is very clearly suboptimal. No drug has been approved for the totality of SSc. The only agents that have been formally approved are ones that target the lung manifestations, the interstitial lung disease. It is an area where there have been many programs that have been in development here, and it's just been tough, which may reflect, again, that this is a complex autoimmune disorder that's not just driven by a single pathway alone and may necessitate something that can act a little bit more broadly. In terms of key differences, insofar as HS tends to be a little bit more neutrophil and T- cell driven with B-cells may be the part that's starting to emerge, SSc is a little bit different, where there's been a long-standing recognition of the role of B-cells, plasma cells, autoantibody signatures that have been present in SSc patients, and where IL-17 may be a little bit more, you know, more emerging. But for both IL-17 as well as BAFF, there are published data sets suggesting concordance between them, but then concordance between the lung symptoms as well as the skin symptoms for SSc. As a note at the start, our goal is to kind of bring together the best of both worlds in these complex immune disorders. SSc, again, presents different profile, but it is a big opportunity where we could be not just first in class, but first in disease, given just the lack of treatment options here for the totality of SSc. Yep. Maybe talk about the trial design considerations, as you mentioned, like very heterogeneous disease. Are there certain subsets that we are targeting with this particular study? How have we implemented the endpoints to try to, again, tease out that effect? Yeah. We've designed the trial, the TibuSURE study, to be 80 patients in total, randomized 1:1 drug versus placebo. Given that it's a rare disease, we're using the high dose, 300 milligrams, every 4 weeks as our dose again, against placebo. The primary endpoint is at week 24. This is consistent with other proof of concept trials in SSc. The primary endpoint is the modified Rodnan skin score. Essentially, you're pinching the skin to kind of measure the degree of thickness it is, like the degree of fibrosis within the skin. As you might imagine, like this all poses, you know, challenges where it is difficult to centralize, you know, that measurement. Again, relying upon expert investigators that we've invested in further training them to confirm that, you know, their measurement lines up with what, kind of an independent body of experts would say is, you know, a given skin score for a given patient. We're also doing CT scans for all patients at baseline, month six and at end of study to be able to track for subtle changes in FVC in lung function based on CT. The eventual primary endpoint for a lung endpoint would need to be FVC, so change in like the vital capacity. However, CT can offer an early kind of glimpse into activity here, be able to detect subtle changes that ideally could be replicated in larger, longer studies afterwards. As noted, SSc has been a tough indication across, you know, for the field, though we take some comfort in the fact that I think the agency recognizes the challenges of SSc and has shown some degree of regulatory flexibility and desire to have new treatment options here. Go from the phase II trial, show proof of concept on the skin score, but then also show benefit on the CT and use that to take that to build the case for a phase III program. That makes sense. Can you give us an update on the trial enrollment kinetics? I know, I think when you first kicked off this study. Yeah. There were multiple large studies that were also enrolling. There was a relatively competitive enrollment environment. What have you seen here over the last couple months that gives you confidence in the first half 2027 timeline? Yeah. It is rare, like a rare disease. When we first gave guidance, we had not yet had the benefit of enrolling anyone in the study, so it was a little bit of an assumption. The initial re-enrollment was slower than initial projections. However, that rate has meaningfully upticked over the last handful of months. We think a lot of that was driven by competitor studies, essentially sopping up additional patients that have now completed enrollment. We're pleased with the re-enrollment that we're seeing, the engagement we're getting from our sites. Our guidance we reaffirm is first half of 2027 for data from the SSc study. That's great. As you mentioned, huge unmet need here. Just remind us how you've powered the study. Like, what is a minimally clinically important difference on Rodnan? Yeah, what would you consider, like, a good, you know, confidence-inspiring result that- Yeah. allows you to advance into a pivotal? Yeah. On the modified Rodnan, the MCID has historically been defined as 3-4 points difference on the modified Rodnan. We've powered it for about that, actually a little bit smaller, like more like 2-3 points delta here. That is again the primary endpoint for the trial. In terms of the CT scans, this is an emerging area. There's not as much experience using like CT scans and quantitative ILD. There are a few trials that have published results here, and essentially the CT scan is to say quantitative measurement of how much of the lung is affected by ILD. Here, 1%-2% difference in terms of the quantitative ILD is considered important and potentially could predict success in a future trial using FVC as an example for an endpoint. We have powered it formally for the modified Rodnan, but we are eager to look at the results for the CT, again, to inform the totality of how effective this drug could be if tested in a larger study. Great. In terms of next steps, you've alluded to this, but yeah, it does seem like an area where FDA has shown some degree of regulatory flexibility and a desire and willingness to work with sponsors. Yeah, just helps think through kind of like next steps. Obviously, a lot's gonna depend on the data. Yeah. Yeah. Yeah, all eyes are on the data, first half, 2027. We are doing the work right now so that we are phase III ready by end of this year, meaning having drug filled into pre-filled syringes, which then we can take into phase III. Now, that would support any phase III plans for HS or for SSc. With a drug like ours where the backbone is a very good IL-17 along with a very good BAFF on the other side, we're planning for success here, with the belief that a drug like this will find a home, if we can take enough high-quality shots on goal, HS and SSc being two examples of that approach. In terms of SSc moving into phase three, you know, we would look to get data from the study first half 2027 and then get the data, go to the FDA, talk through the overall phase three plan, including the endpoint, and then look to start that as quickly afterwards as possible. Got it. We've seen some pretty remarkable data from some of the cell therapy, B-cell depleting- Yeah. therapies in SSc. How does that influence your confidence here with B-cell modulating? Yeah. One of the things that makes SSc challenging is that the longer folks have disease, you can get spontaneous softening of the skin. All right. That complicates interpretation of small open-label trials here. For our trial, we require patients to all have had disease for fewer than seven years, so relatively more recently diagnosed disease to again avoid that problem of, or the issue of like spontaneous skin softening. I think you know, the CAR-Ts and the bispecifics, it's exciting. I think some of the early data look good. The numbers are relatively small. Those programs are probably not relevant or appropriate for a community setting and will probably be limited to more academic settings and likely be used after other modulators and other treatments have been tried here. We don't think a CAR-T is like appropriate for every single patient. It's probably appropriate for a subset of patients, but this is where we would guess a drug like ours, if we can show benefit on skin and lung, we can make a case to try this first before trying something that may be more invasive and more complicated than just giving a simple bispecific. Yeah. That makes sense. Just in the last 30 seconds we have, you mentioned you have two other assets. Yeah. IL-7 receptor alpha antibody and an IL-33 Thirty-three. Antibody. What's the plan? Or, when will we be in a position to have, I guess, more visibility on the path forward for those- Sure. -products? Yeah. We have an IL-7 receptor antibody as well as an IL-33 that we licensed from Lilly and Pfizer respectively. We like the biology for both where there's evidence to support each drug in different indications. How we would develop that on our own I think has been a little bit less clear, especially in light of what we see with tibulizumab, the opportunities in HS as well as SSc and frankly, other indications that could come beyond it. We've tried to be ruthless in our capital allocation and focused our resources internally on the programs that we think have the most value that we can create out of it. We are open and exploring creative ways to advance the other two programs, but Tibu is really where we are placing our focus. Yep. That's where all investor focus is, and we're gonna get data here over the next year. Q4. Yep. Yeah, that's really gonna prove this out. Key data Q4. Sandy, we'll have to leave it there. Yeah. Thanks so much for joining us, Tom. Sounds good. Appreciate it. Yeah. Thanks for hosting. Thanks. Yeah.