I am Sam Semenkow. I am one of the Senior Biotech Analysts here at Citi, and it is my pleasure to be hosting Spyre Therapeutics at Citi's 2026 Biopharma Back to School Summit. I am joined by Cameron Turtle, CEO of Spyre. Cameron, welcome, and thank you so much for being here. Appreciate you having us. Maybe we just start a little bit high level. You made a ton of progress this year across the pipeline. We still do have a couple more readouts through the rest of the year. Can you just level set where the company stands today and what we can expect from you through year-end? Sure. Broadly, our goal is to develop products that elevate the standard of care in autoimmune diseases. In general, our approach to doing that is developing what we think are best-in-class monotherapies, long-acting optimized antibodies against what we think are the best biologic targets in each indication. Then in most cases, we are quite interested in evaluating how these best-in-indication or best-in-class antibodies can be combined together to hopefully do better than we are able to do with the monotherapies alone. I would say in inflammatory bowel disease, that approach and strategy is most mature. That is where we started. We have the three, I would say near top, if not the top three mechanisms in the space, long-acting antibodies against each of them. Over the last few months, including this week, we've shared data from each of them that I think shows that they're at least as good in terms of best-in-class molecules, in terms of efficacy and better dosing than anything else in each of those spaces. At least I think in our Alpha-4 case, maybe can even do better than the first-generation products in terms of efficacy. Then there, we've actually, since about April of this year, we've been enrolling the combinations of those assets, which we think have a realistic probability of delivering efficacy that's above and beyond each of them individually. Beyond IBD, we're first exploring where TL1A should work. I think everyone who has TL1A is interested in its pipeline and a product potential. What indications will TL1A be excellent as a monotherapy, or is it a combination component in these different indications? We're looking at a basket of rheumatic diseases. We reported RA results recently where the drug is certainly active and well-tolerated. We didn't think it was sufficient to advance as a monotherapy in phase III, though we do think it looks like a potentially good combination component. Then later this year, in the fourth quarter, we'll have both psoriatic arthritis, PsA, and Axial spondyloarthritis, axSpA data, where we'll be making the same evaluation. Is this good enough to advance as a monotherapy, or does it make sense to combine with the other great mechanisms in those spaces? Then, we're also expecting data from others as well that inform our strategy. I think in total, there's seven TL1A proof of concepts this year. I've just talked about a few of them. We'll see the HS data shortly. We know it's positive from Merck. Then we expect to see atopic dermatitis as well as MASH from Roche as well in the upcoming months. Again, in each of those indications, we should evaluate whether we think it makes sense to advance our molecule on its own or whether we should consider combination therapies. We made an initial bet in HS already, which is that we might be able to leapfrog the monotherapies by combining TL1A with bimekizumab or IL-17A/F, and we think that's a really exciting trial. Again, like our IBD strategy, combine the best mechanisms in the space, and hopefully we can do better than anything else that's out there today. That is a lot to dig into. Thank you for that. Wonderful. Why don't we start with IBD then? I know you've been asked this a lot, but the SPY001 data was better than I think what we've seen on the approved drug. Then you have the other data sets that are also looking quite competitive. So what is, in your mind right now that we have monotherapy data for all three assets, the best potential combination, and how will you make that determination when you consider advancing one or more of those forward? Yeah. I think the obvious hint in terms of our certainty about which one is best is given by the fact that we're testing them head-to-head right now. I mean, we don't know which of these combinations is best. I think we look at the biology of these and know they're quite orthogonal in terms of how they're benefiting patients with IBD. We've tested these in a variety of animal models and see that all three are additive with each other, so I think there's good reason to believe that they'll be additive clinically as well. In terms of which one, we don't know. That's why we're testing them head-to-head. I think we feel very increasingly good about the safety of all of these. Until recently, I would have put Alpha-4 and IL-23 above TL1A in terms of our certainty of the safety, though I think in recent months, both in our randomized phase II data as well as Merck said in phase III that their TL1A was well-tolerated. I think at this point we feel pretty good about the safety of all of them, and the efficacy of all these is good as well. I have a slight bias towards our Alpha-4-containing combinations because I think it's an elegant solution to a gut-predominant disease to have one agent that's acting in a gut-selective manner and the other being a broader immune suppressant, so you're functionally getting double suppression in the target tissue and then only single suppression everywhere else. I think you said in the past you might just take that best one forward and advance it from there. Is there ever a scenario or an opportunity or even a need in the market where two different combinations might be necessary for some patients to cycle through? As much as I am hopeful that our combinations could deliver much better efficacy than monotherapies today, I think it is unlikely that we are getting to majority patients in long-term remission forever with our combinations. I would love if that were the answer. I just think that is quite unlikely, meaning I think it is still likely to end up being a cycling market, but IBD is a cycling market that is highly concentrated to the best products. If we look over the last decade, the top three drugs have taken almost 70% of the revenue here, and those top three drugs have changed. But as soon as you beat the prior standard of care on efficacy without a safety downside, those drugs take the lion's share of the market. I think it is credible that our combinations have the possibility of beating today's standard of care by a meaningful amount. I frankly think all three of them have a decent shot at that in terms of being those next-generation top-tier products. I think it will make sense to advance more than one if they are all in that top tier. Have you started to outline for us what that bar is? How much higher do you need to go in terms of efficacy above some of these standards of care? I guess it is combination dependent, but how do we start to think about that? Yeah, I think we look at it, two data sets that help us inform what enough better looks like. One is the history of IBD. I think that is frankly more informative, which is, we talked about the transition from the first best products in the space, which Humira, Remicade, Stelara, and now today, we see Entyvio, Skyrizi, Tremfya. These drugs beat that first generation, most cases in head-to-head trials with a delta of about 10% on clinical remission. I think about 8% in VARSITY, plus or minus 10%, depending on which of the p19 versus p40 studies you looked at. That 10% delta is about what we see when we survey gastroenterologists too, in terms of what a superior result to them looks like. I think that is our bar as well. We have to beat the best monotherapies by about 10 percentage points. I think those drugs would then be superior on efficacy, hopefully no difference on safety. I think our combinations are more convenient than any monotherapy on the market today, and I expect we price them in the same range as a branded drug. If all those pieces come together, I think you just have products that are the best in the space. Maybe we spend a little bit of time on SPY003, the monotherapy data that you presented earlier this week. What stood out from that data set? You mentioned safety already being key, but what else stood out for that, convinced you that this is just reinforced that it is a part of the combination? Yeah. I think we started going into all these data sets with an expectation for them, which is in the TL1A and the IL-23 cases, we looked at these classes and see that, one, the molecules within the class are not meaningfully differentiated in terms of placebo-adjusted efficacy in either the TL1A or the IL-23 class. They are more similar than they are different. Particularly in the IL-23 case, the dose and exposure responses are quite flat, meaning we do not see this steep relationship between the amount of drug on board and efficacy. This led us to expect going into our readouts with both our TL1A and our IL-23 that they should perform like the in-class molecules. There is no strong reason to believe that they would be better. That is a bit different than our expectation in going to the Alpha-4 Beta-7 readout, where we did see a pretty strong exposure response for vedolizumab, both in their phase III data and in the real-world setting, which is why we chose a higher dose to go after with our 001 readout. Again, all of these are 40-odd patient open label studies, and so we take them with a grain of salt. But I think it supports the idea that the Alpha-4 might be delivering greater efficacy, and then the TL1A and IL-23 are similar. What about the potential for ADAs for the TL1A? I know that that's been a concern for some of the assets, but perhaps less so for you. Just walk us through that. Yeah. I think in general, I'm not convinced yet that we know that immunogenicity of TL1As has caused a reduction in efficacy. At least in the data we've seen to date, it is one of the best classes in IBD, if not the best class overall. I think there's some question as to whether the maintenance data is as good as you might hope it to be, and therefore maybe that's an immunogenicity issue that's causing the reduction in efficacy in maintenance. I'm not sure that's necessarily true as they're either half-life issues in terms of dosing interval and these molecules or potency as well. Any of these things could basically lead to an incomplete target suppression in the maintenance setting that may not be ADA related. We'll see more as we get, I think, these phase III data sets from some of the other sponsors, especially Merck, for example, doubled their dosing frequency going to phase III in the Crohn's Disease Study, and I think that'll give us an indication of whether it was underdosed in maintenance and can you get greater target capture. Often you can dose through an ADA issue, and so we might see that in the Merck case. So I'm not sure it's an issue yet. I don't think we've, in terms of the range of the TL1As, ours is towards the lower end, more comparable to the Merck and Sanofi Teva Molecules. Some of the others have much higher rates of ADAs, and I think they would make a strong case that they don't think it's impacting their efficacy. You brought up Crohn's. At what point do you think that Spyre could consider moving into there? What do you need to see? What data set do you want in hand before that? Yeah, it's our strong expectation that whichever programs advance from this SKYLINE study, we'll advance in both UC and Crohn's. We know each of these mechanisms work in both UC and Crohn's, and I think over the data over the last few months, both from Johnson & Johnson and AbbVie, from the DUET studies and the Target CD study, give us pretty good confidence that combinations work quite similarly in UC and Crohn's as well, including Alpha-4 Beta-7, including IL-23, and including TNF. I think mechanisms that are the same as or similar to us, I think we have good confidence that they're going to show additive efficacy in both of these indications, and so our expectation is whichever winner or winners we're advancing from the SKYLINE study will advance in both UC and Crohn's. Got it. Okay. You've alluded to this in the beginning, but when you think about the competitive landscape, there's a bunch of different combinations out. Some of them are oral and injectable, some of them are clearly not fit for purpose necessarily like yours have been developed. Some are bispecifics. What is specific for why Spyre chose the co-formulation approach? Start there, and what are the advantages there versus all these other approaches? Yeah. I think it's fair to say that we were a little bit at the right place at the right time when VEGA came out. Basically, we've been working in this space for 30 years, looking at different mechanisms, and hit this therapeutic ceiling. Then the combination comes out and shows that if we add these mechanisms together, we break that. And we were there picking development candidates against the three best mechanisms in the space and could pick them not just for best in class for the individual molecules, but could pick antibodies that co-formulate incredibly well at high concentration, that we could run combination tox for, and prove that they are well-tolerated together to run these animal pharmacology studies as well. I think that setup leads to what the differentiation here now, whereas most other players in the space basically were combining what they had in hand when VEGA came out, and that has tended to be a mix of things. Includes orals and injectables, which some people for one or the other, no one wants both. I think that is tricky from a pricing perspective, combining antibodies with different half-lives, so the dosing intervals are challenging. Combining antibodies that were not designed to co-formulate together, it is certainly no guarantee that any two antibodies are going to be stable with low viscosity in the same pH and excipients as each other. We have that. It is not guaranteed that others get there. Our ability of having these all at the same time has let us run this, what I think is a pretty efficient and innovative development program to get them there quickly. On the regulatory side, how should we think about demonstrating the efficacy from each of those? What is the latest from FDA on requirements for proving the efficacy from each component? Yeah. I think in general, we believe that we have to test contribution of components. You need to demonstrate the monotherapies beat placebo, and that the combinations beat the monotherapy components. Statistically, benefit would be the best, of course. That is the design of the SKYLINE study is to accomplish that. We have all three monotherapies against placebo, and we have all three combinations that can be compared against placebo as well as their monotherapy components. Obviously, we are hopeful that we are going to hit that in this trial, and I think if we do on any of. We have three shots at this as well. I think that sets up a relatively straightforward pivotal path. I think we actually have a reasonable idea of what that path looks like, learning from precedent in the space, most obviously Johnson & Johnson, who they ran a number of phase II studies with their combination, aiming for contribution of components. Frankly, did not quite hit it in terms of in a single study showing that the monotherapies both beat placebo and then the combos beat the monos. That never was quite accomplished on a primary endpoint, and yet their phase III looks pretty straightforward. It is a two-arm phase III. It is actually the first non-placebo phase III in IBD. I think that is a very important precedent and actually helpful precedent because a non-placebo controlled phase III both gives you an active comparator, which could be incredibly helpful from a pricing and access perspective. No placebo phase III is going to enroll much more quickly than a placebo-controlled phase III. How much risk do you think in your study there is to proving, to hitting on contributions on components? I think the study is well designed to achieve the deltas that we expect to see, and we know pretty well what the monotherapies will show versus placebo based on our data and others. The combination additivity, these are all first in class. I think we know we have a reasonable estimate of how much we think they will win by, and we're testing that. We also have three shots at it. I think that gives us pretty good odds of having at least one that shows it. Is there anything else we're missing from the IBD conversation, do you think, before we move into rheumatology? I don't think so. I think we've proven all the pieces of our portfolio work. I think we'll see how good the combinations add up. I think all the evidence is pointing towards these are likely to provide some additivity. I think additivity in the 10% range, I think is very achievable between these multiple mechanisms, and I think that would be enough to shift the market towards these products in a meaningful way. When do you think we could get more granularity on when the study will read out in 2027? Yeah. We've been enrolling the combo since April. We're five months into the Part B enrollment. I think we feel very comfortable with our 2027 guidance. We'll probably provide a narrowed window, I would expect towards the end of this year or early next year when we're a bit further along. Okay, perfect. Looking forward to that. Then maybe let's just move into the rheumatology piece and beyond, including HS now, I guess we have to say, beyond IBD rather than rheumatology. The RA, maybe let's just start there. That data you noted was clearly active, but maybe not at the bar that you were looking for. But you mentioned interestingly about a potential combination approach. How should we think about just combination, I guess, with your second SPY072? I think for any combination, best case scenario is two active agents, neither with safety concerns. Challenge in RA is there aren't very many of those. Most things in RA that have demonstrable efficacy and beat placebo also carry meaningful safety risks. We have actually seen combination trials run in RA previously that weren't successful, that saw some additive safety concerns when mechanisms that individually had them were added together. I think in RA, we're a little more cautious about combining TL1A with other mechanisms. I think if we didn't have so many other exciting things ongoing, that would be a path that we certainly could have or might have considered pursuing. Today, though, I think we want to see the results in PsA and axSpA. There, I think the combinations are much more obvious. We already have the agents that would be most obvious to combine them with. Same in HS. I think if TL1A is in the range of Bimzelx efficacy, then we're combining it with Bimzelx or a long-acting version of Bimzelx, I think that's credibly likely to be the best agents in those spaces as well. RA is trickier. I think it's something that we could explore over time, but it's not something that we thought this is an immediate priority for us. We had talked about this. If RA worked or didn't work, how much does that read through to psoriatic arthritis or axSpA? I think there was a general consensus that if it worked in RA, it should work in psoriatic arthritis and axSpA just based on the preclinical data you have. It went the opposite way. It worked, but not quite as much as you want. So what does that read into the expectations for the psoriatic arthritis and axSpA data later this year? Yeah. There's incomplete correlation between these. Sure. The TNFs and JAKs work across all three. I would say this TL1A is active in RA. I do expect it to be active in PsA and axSpA as well. We do see that there's decent differences between these indications in terms of individual mechanism efficacy. IL-17s and IL-23s would be the classic case that don't work as well enough in RA alone, but they're the leading products in PsA and axSpA. I think there's some similarities between the TL1A activity on Th17 cells with the IL-17 or IL-23 paths as well. We certainly don't write off the potential that TL1A could work in these indications well enough as a mono. I think that's still a reasonable possibility, and I think in many ways, I might actually increase my probability that it's a great combo component. It's effective on the joint scores, and it doesn't have a safety downside. I think it's actually a good bet. Maybe with psoriatic arthritis first, let's say it works. It meets that minimum bar that you've set for moving it forward. But you've made this point several times that you have the IL-23, you could do a combination, and we know IL-23 works. Is there a possibility that you could run that combo study in addition to the monotherapy study to really figure out if this is worth advancing combo? Because I think psoriatic arthritis is one of those, you cycle through a lot of therapies, it's kind of in a little way similar to UC, so why not just raise the bar there? Yeah. Actually, it's something we think about in every indication, as you can imagine. I think our Alpha-4 data is amazing in IBD. That could be a great monotherapy agent as well, but we feel quite confident the combos will add up, and they're not different in timeline, relatively, compared to the monotherapies. That has led us to prioritize the combinations there. In the rheumatic diseases, first we need to see how good TL1A is individually. So we need this proof of concept, and then how good it is, I think, will determine does it make sense to advance as a mono? Does it make sense to advance as a combo? Maybe there's a small sliver where it could make sense to do both. We'll see, depending how good the data are. HS, same decision, right? I think we'll see soon enough how good TL1A is relative to Bimzelx. I think if you have Bimzelx-like efficacy with safety that could be cleaner than Bimzelx, frankly. I think we would have the most convenient product in the space. It could be a leading monotherapy in the space with high probability. A combo still could beat it, but in an immature market that is growing, it may actually make sense, it could make sense to have both. Right. For HS, when we see that Merck data, they commented on HiSCR50. I think we know that the field has sort of moved beyond that to HiSCR75. When we see the detailed data, what are you hoping to see? What magnitude of efficacy would be convincing for you? Yeah. The question for us is it good enough to advance ours as a monotherapy? That's the decision for us. It sounds like they're advancing theirs, which I suspect means it's pretty close. From a powering perspective, we thought it had to be pretty close as well. I think we're encouraged by that. I think the combo's always going to make sense. When we test among dermatologists, beating Bimzelx or TL1A by 10 points is enough. It's like the IBD answer as well. It's a very serious disease. Patients and physicians are looking for greater efficacy. I think combining top two mechanisms is a pretty good approach for that as well. That's what we're looking for is how close is the efficacy to Bimzelx, basically. If it's in the range, I think that'd be very exciting. You mentioned the long-acting IL-17 as a potential. That seems feasible. Would that be, I guess, a partnership, or do you have one in your own pipeline? We have our own. You have your own. Our SPY007, our coolest name asset, is a long-acting IL-17. We are running the current study with SPY072 plus Bimzelx against Bimzelx alone. Basically, it will tell us how much better is the combo than the current standard of care. Then if that is successful, we would plan to advance co-formulated combination of our TL1A and a long-acting IL-17. Got it. Okay. HS is difficult. We have seen these trials with the placebo arms behave not as you would like them to several times now. How do you think about managing that with this market, just because it has so much heterogeneity? Yeah. So in this initial study, it's actually just a combination against Bimzelx, right? I think we'll have a pretty good sense. I think we roughly know where Bimzelx will land. We think we know what we need to beat it by. You made an interesting point about the field moving from HiSCR50 to HiSCR75, and we generally agree. So you'll see in our study design, the primary endpoint is HiSCR75. I think we've learned from IBD that combinations tend to outperform more on the deeper endpoints, which I think makes sense. Monotherapies only have a certain level of efficacy. The combos get to a deeper level of response or remission. I think that we roughly know where a HiSCR75 is going to land for Bimzelx. I think we'd be hopeful to beat that by a meaningful amount. And so you have the psoriatic arthritis, the axSpA cards to turn. You have HS starting up, but you mentioned plenty of other potential indications from third-party data that you could consider. How are you thinking about capital allocation going forward, I guess, outside in the rheum and derm space or beyond? How many of these proof-of-concept studies could you reasonably start up with your current capital? Yeah. So, as of last quarter, we have $1.1 billion on the balance sheet. And we say the runway's into second half 2029. That, of course, includes all of these phase IIs and well more than a year beyond, a couple of years beyond all of them. So I think we're very well-funded for all the proof of concepts. I would even say we've prepaid some amount or pre-funded some amount of phase III work. Which phase IIIs it'll be, we don't know yet. I think this year we're going to have a bunch more monotherapy readouts as well. Next year, we could have as many as four combo readouts, three in IBD and one in HS. I think those are going to be very high-priority products to fund. I suspect if we have an indication leading product, those will be trials that folks are going to be willing to fund. So far, we've been 100% equity to date. I think as we get into late-stage development, more opportunities are available. I think equity will continue to be a part of the story, but I think we'll have lots of choices. Okay. I guess then, you have a lot of choices. How do you prioritize the indications? Are there any certain criteria when you think about what you need in terms of size and competitive landscape? Yeah. I think in all of these markets are all large. HS is the smallest, and I think by when we're launching, we expect it to be closing in on $10 billion. That's the smallest of the markets we're looking at. So, I think if we have indication-leading products in any of them, it's going to be an obvious decision, and we would look for the ROI in each of them individually. When you think about the business, let's call it five years into the future, you would have presumably multiple phase III running in IBD and hopefully other indications as well. What do you start to envision for the business from there? Yeah, I think the opportunity here is vast. I think the potential for indication-leading products in some of the largest markets in our business, I think we have many shots at that, and I think they're reasonably high probability shots at that. I feel pretty good about our ability to go execute on these phase IIIs. Frankly, the phase IIs that we're running are very large and complex relative to most phase IIs that biotechs take on. So the jump to phase III is quite a bit smaller here. Our phase III and our phase II in IBD is 300 sites across 30 plus countries. It's a phase III sized phase II. I feel confident in our ability to scale up and do that. In five years, we'll definitely be thinking about, if not actively commercializing things as well. Then, we need to think about what things can we take on ourselves. Can we really go build sales forces in rheum, derm, and IBD? We'll see. But I think if these products deliver what I think they could, I think we'll have lots of choices. Your play is best in class efficacy, almost across the board, right? That's sort of how you're going to win this share when you think about competing against these large pharmas who own a lot of these markets right now. Yeah. Each of them is a little bit different, but yeah, in IBD, the products that win on efficacy in a meaningful amount take the lion's share of the market. I think we have three. Today, I wouldn't trade one of my combos for anything else in development. I'm not promising we're going to have the top three drugs in the space when we ultimately get there, but I think there's a good shot we'll have at least one, if not more than one in that category. Just a quick AI question, if I may. How is Spyre leveraging this within the business? Are you building new tools, new drugs with it? Are you leveraging it for productivity? I'm just curious how it's been most impactful for Spyre. We could use it, I would say almost every function in the company uses these tools all over the place, from accountants to lawyers to clinical development and regulatory folks. Everyone's using the tools for various things. I would not say any of our antibodies are AI designed or anything like that, but I think these tools are getting used ubiquitously throughout. I frankly think it's easier to incorporate new tools in a small growing company. Everyone here is excited about. Everyone's busy. We're doing a lot of complicated, hard trials, and folks that can find ways to be more efficient in their day-to-day is great. Frankly, it just means we grow slightly slower, and our head count growth is slower than it might've been if we didn't have these tools. Fair enough. Cameron, we've been very efficient with our time. I want to just offer you an opportunity to say any closing remarks and recap what's next for us, as you will. Yeah, sure. I think it's one of the most exciting times in biotech's life here, which is figuring out which of our products could be indication leading across, as I said, some of the largest markets in biotech. I think we have good shots at having these best in indication products across IBD, across HS, and we'll see in the rheumatic diseases in the next few months as well. So it's incredibly exciting time. A lot ahead. Great. Well, thank you so much. This has been wonderful. Appreciate the time. Thanks, Sam.