Great. Good morning, everyone. I'm Alex Thomas, a biotech analyst here at Stifel. Happy to have Cameron Turtle with us to kick things off, CEO of Spyre Therapeutics. Maybe just to start, I'll have Cameron give a brief overview of the company, and then we'll get into a Q&A. Obviously, feel free, if anyone has any questions, to jump in as well. With that, Cameron. Thanks, Alex, for having us, and good morning, everyone. Our objective at Spyre is to look for what we hope are indication-leading products across a range of autoimmune diseases, specifically inflammatory bowel disease and then a set of rheumatic diseases. In inflammatory bowel disease, we're developing three long-acting antibodies against what we believe are the best targets in IBD. That's alpha-4 beta-7, TL1A, and IL-23. Each of these targets, we've engineered antibodies that have approximately or more than three times the half-life of first-generation products that we believe enable us to deliver products with substantially more convenience than first-generation products and potentially able to match or exceed the efficacy of first-generation products as well. I actually think in today's market, if we were to launch those antibodies, I think they would be indication-leading products in inflammatory bowel disease and could be blockbuster products on their own. That said, I don't think that is the future of inflammatory bowel disease. We, and I think most sponsors who are serious about the future of IBD, are exploring the idea that combination therapies have the potential to dramatically improve efficacy in inflammatory bowel disease. We are uniquely positioned to combine these long-acting antibodies to make combinations that are more convenient than any of the monotherapies on the market and hopefully deliver substantially better efficacy than what we have today. Yeah, I think with that trend that you sort of talked about, why are combinations really the future? What is the white space, and sort of what is the trend in IBD more broadly that you're fitting into? Yeah, so I think maybe just the background here is we've been looking for kind of the silver bullet for IBD for decades and not found one. We've tested dozens of different mechanisms. We now have about a half dozen approved classes of drugs. None of them get above about a 25% clinical remission rate. I don't think that's surprising because this is not a monogenic disease or a single pathway disease. There are many things that drive IBD. The idea that one mechanism is going to completely cure it is highly unlikely. The idea that blocking more than one pathway could have incremental or additive benefit is supported by human genetic evidence, human tissue evidence, animal studies. All of these things have supported this, plus a whole host of real-world evidence where clinicians test multiple mechanisms and for years have seen that they provide additive efficacy and in most cases don't see meaningful safety downsides. This has led really the whole field to start testing this, probably most dramatically supported by the first randomized study in the space, which was J&J's Vega study, where they tested two of their mechanisms together and got almost directly additive benefit in naive patients. Yeah, I think that gets to the other debater or question here that I think we still do not fully know the answer to, which is co-formulations, combinations versus bi-specs when you are thinking about multi-specific targeting. Why is combinations the approach that you have focused on? Yeah, so we thought a lot about this when we were starting with Spyre and debated kind of making these as multi-specific antibodies versus co-formulations and obviously landed on the co-formulation approach. The kind of first principles here is that bi-specifics are great and really elegant solutions when you're trying to bring two targets together. I think in a number of oncology applications, that is a clear and obvious answer. In the case of ADCs in particular, bring two things together and lead to the biology that you'd expect. That's not what we're trying to do in these diseases. We're trying to block two different pathways independently. I think actually bringing these things together could actually have deleterious effects. I mean, in particular, when you have a membrane-bound target that's on the surface of immune cell and then you're bringing an inflammatory signaling molecule to it, I think that's more likely to have a negative impact than a positive impact. Just first principles, we thought that does not make sense in this case. Also, the idea that bi-specifics always have the same properties as co-formulations could in terms of fully blockading each pathway, I also don't think that is true. I think that you carry substantially more risks with multi-specific antibodies than you do with co-formulations. Notably, and I think maybe the class that's worth going back to look at, we made more than a dozen TNF bi-specifics a few years ago. None of them made it to phase III development, and they all were discontinued for one of two reasons. One is that they were highly immunogenic. They formed kind of large immune complexes that led to rapid clearance of these bi-specifics, or they just didn't bind the two targets in a multi-specific construct as well as they did separately. We thought the lowest risk way of getting kind of the best engagement of two separate targets within one product was to co-formulate two antibodies. We've shown that we can do that at 200 mg/mL, really the high end of what you can achieve for any formulation with all three of our different antibody combinations. Yeah, and you alluded to Vega, which was really that first combination study from J&J in the naive population. Can you talk a little bit more about the key learnings from that and sort of the evolution of Vega then to Duet and how that's different and what the expectation should be? Sure. The Vega study was the first randomized combination study. It was testing the IL-23 TREMFYA combined with SIMPONI golimumab in naive ulcerative colitis patients. The simplest result is that they roughly doubled the clinical remission, kind of about 25% on each of the monotherapies and almost 50% on the combination arm. It really shows that in that first-line naive population, the combination is dramatically more effective. I actually think that learning will not change regardless of what we see in these upcoming trials, that in first-line patients hitting multiple pathways at the same time is dramatically more efficacious. In a disease like IBD that is incredibly hard to manage, costly, and some of the consequences of the disease are irreversible and you want to hit the disease hard at the beginning, combos are clearly the right answer. On the back of that success, J&J launched three additional trials. They launched an Affinity trial in psoriatic arthritis, where we've already seen the data. We'll probably talk about that. They launched two trials again in IBD, one in ulcerative colitis, one in Crohn's, called the Duet studies. All three of those studies were done not in naive patients who hadn't seen biologics before, but all in patients who've all been exposed to prior biologics. I think that is really the key difference. There are other differences in terms of the ending, the time point, and other things, but I think really the key difference is the patient population. What's a good outcome then for Duet? I think both the Affinity trial and the Duet trials are one of the toughest setups for combo. It's basically testing a TNF combo in a patient population where everyone in the Affinity trial had failed the TNF. In Duet, we would expect almost everyone has also failed the TNF. I think it's a pretty tricky setup for a combination to work. I also think a refractory population, we always see that the remission rates come down. Even with monotherapies, we would expect it to be lower. I think what we think about in terms of a bar for success for combos overall, and I'll come back to Duet, is about a 10-point delta relative to monotherapies. In IBD, a 10-point delta is clinically meaningful. It has led to dramatic uptake of products in the past. That's ENTYVIO beats HUMIRA by about 10 points, and the P19s beats STELARA by about 10 points. All of those had led to the products that won by that amount being high single-digit billion-dollar selling products in this space. I think you need about a 10-point delta overall. I think that needs to be in a mixed naive refractory phase III study. You get about a 10-point delta. I think that's going to be a mega blockbuster product. Yeah, and I guess with that, and Affinity I think is part of the conversation here, is statistical significance matter? Not in a phase II study, really. I think in general, you need to be convinced that in a phase III study, you would get that 10-point delta in a mixed population. I think that's what everyone should be interested in is, OK, what is going to be the labeled delta between that product and what's on the market today? Again, just coming back to the TREMFYA, SKYRIZI example, those things beat a biosimilar by 10 points, and they're going to be high single-digit billion drugs. If a combo beats a branded product like TREMFYA or SKYRIZI by 10 points, it's a whole different ballgame in terms of what that's worth. Yep. Going back to Spyre specifically, you do not have a TNF. You have an IL-23. Why does this matter to Spyre specifically? Yeah, I think in general, I mean, we picked the targets for our combinations intentionally, clearly. I think alpha-4 beta-7, IL-23 are probably the two safest classes in IBD in terms of the consequences of blockading that. They're both efficacious with very little safety downside. And then TL1A so far also looks incredibly clean, also with great efficacy. I think all three of those targets are superior to TNF. Alpha-4 proven to be superior to TNF head-to-head. And TL1A and IL-23, I think, is likely the case as well. I think a TNF combo in a TNF refractory population, it's a tough bet. I think our combos in our population, I think, is a much stronger bet. I think the other interesting question coming out of Duet is about contribution of components, right? What this means for the field for potentially what a phase III design might look like. I guess assuming Duet shows a 10-point delta and there's a path forward to phase III, what are you looking for in terms of FDA feedback or a phase III design to sort of understand what you might need to do in your phase II study to then have a cleaner phase III design? Yeah, so I think this is the first time that folks are developing combinations in IBD. Kind of the FDA and the GI division, this is their first time reviewing these as well. I think we're all kind of going through this path together in terms of understanding what's expected. I think everyone, again, who's serious about developing combos in IBD is roughly following the same blueprint, which is aiming to solve this contribution of components design. J&J did it roughly in Vega. They're doing it pretty robustly in the Duet studies, though I would say in the harder population to try to do it in. I would say our study is aiming for it. AbbVie kind of as well and Lilly kind of as well with how they're pursuing this. I think we'll see. Not all of these are the same level of robustness, but I think over the next few years, we're going to get to see quite a few readouts of different combinations and then see how the FDA says, OK, is that the appropriate bar to hit in phase II? I think we're solving many of the questions in our current phase II study. I think there's quite a few ways that we could address any unanswered questions in a pivotal study. Yep. Yeah, I guess can you maybe elaborate a little bit more on your phase II design and the questions that you're seeking to address there? Yeah, so I think our phase II accomplishes a handful of things. One, we're dose ranging our monotherapies in the study. Two, we're aiming to solve contribution of components. I think those are the two key things that we're aiming to solve in this study. We're doing that with one placebo, kind of the three monotherapies, and then the three combinations clearly designed to achieve contribution of components. What we know we're not solving is dose ranging the combinations. That is one thing that we do expect to have to do going forward, to dose range the combinations of our products in pivotal study. Maybe one more question on Duet. Sort of we're also going to get a Crohn's cohort here. What are your thoughts and expectations coming out of Duet for Crohn's? Yeah, I think Crohn's is much harder to benchmark. We don't have Vega. We don't have prior studies in Crohn's patients either. In some ways, it can be a more serious disease. We see greater biologic penetration. Some would say the unmet need is even larger in Crohn's. It's also true, I think, that the endpoints are a bit noisier in Crohn's than you see, which has a more kind of objective endpoint than Crohn's disease. I frankly have a harder time giving a specific number or benchmark that we would expect to see in Crohn's. I think we'll all learn a lot from what we see in Duet. Yep. I guess moving on to your specific pipeline, you've now generated phase I data for your alpha-4 beta-7, your TL1A, and your IL-23. I guess two TL1As. We'll get to the second one in a little bit too. I guess maybe at a high level, can you talk about the properties that you've seen in phase I relative to the first-generation antibodies? Yeah, I think in general, so for our alpha-4 beta-7 and our IL-23, I think the design is quite similar where we're aiming to be very comparable to ENTYVIO in the alpha-4 beta-7 case and very comparable to SKYRIZI in the IL-23 case in terms of potency, binding, specificity. I think those two molecules are quite similar to their parental molecules, except they have more than three times the half-life. I think we can dramatically reduce the amount of drug that we have to deliver. That's both in the induction setting, how much we have to give to get to the same coverage. In the maintenance setting, we can have a far more convenient product, give it on a quarterly or twice-annual basis where those first-generation molecules are delivered as frequently as every two weeks. I think that's kind of the case for those two. Our TL1A is a bit different. Both our TL1As, we didn't say we want to be similar to any of the first generation TL1As because we thought the properties of those is not what a best-in-class TL1A could look like. Specifically, we have a molecule that compared to some of the first generation molecules, substantially better potency, substantially better bioavailability or formulation, substantially better immunogenicity, and three times the half-life compared to any of them, more than six or seven times the half-life of one of the first generation TL1As. I think across the board, we have what we think are kind of optimized versions of each of these targets. I think it will be hard to make a better biologic than the ones that we've developed against each of these targets. Your phase II study, we talked a little bit about the design here, but I want to get into the first set of readouts next year, right? You're going to have monotherapy data, open label now for all three of these antibodies. What does a good outcome look like for these three updates next year? I guess maybe we should expect them to come separately just because this is sort of a, as you've enrolled, gotten past the phase I, you've enrolled these cohorts as well, right? Yeah, so we started this trial back in June with the alpha-4 beta-7, added the TL1A a few months ago in Q3. Then we just had our IL-23 data a couple of weeks ago or maybe last week. We'll be adding this molecule to the study as well. All three will be in the study here in the upcoming weeks. Yeah, we will expect to read out all three of these open label cohorts next year. It is possible actually, I mean, just because the gap between when the alpha-4 and TL1A started the study, they actually could finish quite proximately together. We could do those. I do expect the IL-23 is a couple of months later than the first two. In terms of what we're trying to see, I mean, as I mentioned, these molecules are targeting the same biology as the first generation products. I think it's highly likely that we will have at least the same level of efficacy as the first generation molecules. For each of them, we're dosing them a little bit differently. I think in some of the cases, there's an opportunity to potentially have better efficacy than the first generation molecules. A small open label cohort, I think you can only get so much definitive information from that type of study. I think in general, what we're looking to see here is these things are at least as active as the first generation molecules, prove that their kind of interim data, they're safe and efficacious in terms of affecting this disease. I frankly think these set a floor value for Spyre that I frankly think is above where we trade today. I think a quarterly or twice-annual ENTYVIO is a valuable asset. Same thing for TL1A and IL-23. I think those all come next year and should frankly, I think, raise the baseline value of the company. I also think when you start seeing those data, it will be hard to not think about what one plus one looks like in terms of having a best version of each of these things and what would it look like if you added these together in terms of the level of efficacy and safety you could see. I think that will be hard to ignore when you read those out and then you're less than a year away from the combination data sets. You alluded to the dosing and your alpha-4 beta-7 asset. You are seeking to dose it at a much higher exposure than ENTYVIO based on the data that we've seen from phase III there. Should we expect to see better efficacy or what are your thoughts? I think it's a totally reasonable hypothesis, which is why we're testing it. In both the phase III data for ENTYVIO and then even in the real-world data, they see that patients that have higher exposures of the drug have a much higher rate of clinical remission. We think this molecule is very well tolerated from a safety perspective. We thought the rational thing to do here is to increase the dosing. It's actually what many physicians do in the real world too. They double the dose or have the dosing frequency of ENTYVIO in the real world because they believe that they could get better efficacy than the labeled dose. The goal here is to make the best possible version of each of these targets. We think the rational thing to do with alpha-4 is to test that higher exposure. We'll see that. It will get a hint at it next year in the open label data. We will see the full thing when we read out the full readout from SKYRIZI. How functionally do you roll into the combo and placebo-controlled cohorts? Yeah, so part A to part B is a seamless design here. We are not going to wait for all the data, pause enrollment for five or six months while we are kind of waiting for everybody to get to the three-month induction and then wait a few months till we have the data in-house. We expect as soon as we finish enrolling part A to start enrolling part B seamlessly. OK. I want to pivot now to your second TL1A. I think one of the questions heading into your phase I study for your TL1A was why move forward two assets. Maybe can you take a step back and answer that question and sort of what came out of that phase I? We'll talk about where we're going forward. Yes. In terms of why we took two, as I mentioned, for both our alpha-4 and our IL-23, we were really following the blueprint of kind of proven ways of targeting each of these mechanisms. Whereas for TL1A, it was de novo, right? We wanted to kind of completely novel molecules because the ones out there we did not think had the best properties. We took two forward. We knew that there is a risk for TL1A like there is for the TNF class. These molecules have some similarities in terms of their structure, in terms of their signaling. We know that there is an immunogenicity risk for TL1A that can lead to kind of performance of your antibodies that is lower than you would expect. That is why we took two into humans. You really do not de-risk immunogenicity in preclinical work very well. We took two into humans. We got the best possible outcome, which was two great molecules. That set us up for kind of an interesting strategic opportunity here, which was to take the molecules into two separate studies. This means in the IBD study that we just talked about, we're using one of the two molecules. Then we're taking the second molecule into a basket of rheumatic diseases. This opens up in the long run some commercial flexibility in terms of kind of there's some pricing optionality and some kind of ways that that could be useful in a commercial setting. In the more intermediate term, it actually creates some optionality from a strategic perspective as well, which is that these molecules, we can partner sell one of the assets without impacting the other side of the business. I think that provides quite a bit of optionality for us in the next year or two as we start to read out these phase II data sets. Then the decision to go as a first-in-class TL1A into rheumatologic disorders, can you talk a little about the level of evidence here for TL1A targeting and how that maybe compares to IBD? Yeah. So I mean, we spent the first couple of years that we were at Spyre kind of deciding what to do with our TL1As beyond IBD. I think we and everyone else who owns TL1A looks at there's evidence for TL1A in more than a dozen different indications from human genetic, human tissue, animal studies that suggest TL1A could work in all these indications. We spent a long time deciding what we thought were the most attractive and came up with these rheumatic diseases really at the top of the list. Scientifically, we think it's the strongest. The mechanisms overlap substantially with IBD, TH1, TH17-driven diseases with some additional benefit on fibroblasts and fibroblast-like synoviocytes, which are known drivers of these rheumatic diseases where we know TL1A has an impact. It might not just be TNF-like. It actually could be superior in these indications. We really thought this is the most compelling set of science. We also like the commercial opportunity here is vast. Combined, these are $30 billion of market. The products in this space almost exclusively have black box warnings or substantial monitoring requirements. Almost all of them are dosed on a weekly or biweekly basis. We are looking at a new mechanism that we can dose quarterly or twice a year that so far has no meaningful safety concerns. Granted, it's only in phase II studies to date. We think the evidence is that it could be at least as good as these other classes from an efficacy perspective. We thought that was a super compelling case. We were frankly a bit surprised that we were going first because we thought this was. We're still not anymore. Yeah, exactly. We're still first. We're just not only anymore. I think we launched this study a few months ago. We started dosing across all three rheumatic diseases, RA, PsA, and axSpA back in Q3. Shortly after we started, others that own TL1A said that they were going to enter the space as well, which I think is nice validation that we picked right. Especially given that being first and with the convenience advantage we have, I think it also proves that it puts us in a great position. I think the next question here is how robust are these studies? Maybe you could walk through the design. How confident are you that we're going to have a real answer when we read out some of the data sets next year? Yeah. In terms of the design, it's a basket study of three diseases with sub-studies in each of the indications. In RA, it's 120 patients. It's two doses. It's 40, 40, 40—40 on high, 40 on low, 40 on placebo. In psoriatic arthritis and axial spondyloarthritis, it's just a high dose and low, two to one randomized. It's 60 on drug, 30 on placebo in PSA, 50 on drug, 25 on placebo in axSpA. The end points here, each of the sub-studies is, I would say, nothing novel in terms of the design of these. There's kind of well-worn paths for development in each of these indications. These are all proof of concept studies in relatively broad populations that are mixed between folks that are naive to advanced therapy or that have had prior biologic therapy, which we think is the right choice for a proof of concept study. What we're looking to see here is kind of do we have that competitive profile in them. We're looking for kind of a level of efficacy that is in the range or as good as what's out there. If we have that safety and convenience advantage, we think this would be a big product across these spaces. With the strategics now coming into the space, you were first, but are you confident you can maintain your lead? I think we probably should be a couple of years behind, frankly. These companies have had these assets for a while. We should be starting this trial a couple of years after them. Yet we're ahead. I think a basket design is the most efficient way to do this. This design allows you to activate a site once and you have the same investigator running all of these studies. I think it's by far the most efficient way to do this. I would be surprised. I think guidance would suggest that we're going to get the readouts from these studies first. I think it's on us to not lose the advantage that we have. I think we have a product that I think is superior. At least the properties we've seen so far are better than the first generation molecules. We're starting at least a few months ahead of them. So it's ours to lose, I guess. Yep, yep. You alluded to this, but you come to the end of next year, you have data across these six readouts between U.C. and the rheum indications. What does the strategic path look like? Are you in a position potentially to make a decision on your path forward at O72 here? How are you thinking about the end of 2026? Yeah, no, I think it's an incredibly interesting period and exciting time for the company overall. I think one of the reasons that we did this most recent financing is to give us a huge range of strategic flexibility. We have nearly $800 million on the balance sheet. This takes us well into the second half of 2028. I think arguably we could extend it from there if we needed to. This enables us to go through six readouts next year, turn over a bunch of cards in terms of seeing the quality of each of our products. It also puts us right on the doorstep of seeing our combination readouts in 2027 as well. I think between these two studies, there's $60 billion of commercial market that we're going after between IBD and rheumatic disease. I think we have many shots that could be indication-leading products across these. The revenue potential, I think, is substantial across the cumulative nature of this pipeline. I think we'll get to decide in terms of which things we think have the highest ROI to take forward ourselves. Because of how we've designed the study and used the assets, I think we'll have some flexibility in terms of saying, we want to do this. We want to partner on this. These things do not meet our bar in terms of what would be attractive enough to advance to phase III. Maybe I feel like I should ask this question as well. Going back to the IBD side of things, I think we talked about this. UEGW this year was about a lot of orals, a lot of different new oral mechanisms that are moving into the space. You have ICOTR/KINRA. You have the Obefazimod data. We had the Morphic data, the oral alpha-4 beta-7. We talked about bispecifics versus combinations. Where do you see orals fitting into IBD versus where you're going in the future? Yeah. I think one of the KOLs closed one of the panel sessions, which I think the quote that sums it up best, which is he functionally said, this is the last conference that we'll be talking about monotherapies as the main event. I think that's true. I think our monotherapies, when we test kind of a quarterly or twice-annual injectable relative to a daily oral, it would be preferred. The injectable is preferred by the majority of patients. I think if we advanced our monotherapies, these versions of alpha-4, TL1A, and IL-23 relative to the daily orals, I think we would have the preferred products. That said, I think if you can meaningfully step up the efficacy, I think convenience is substantially less interesting. I think we have the best approach at developing these combos that have a real potential of having additive efficacy without a safety downside. Because we can co-formulate and inject them as a single shot, we can price them as one drug as well, which I think is something that most other players in this space have yet proven they can do. Great. Maybe with that, Cameron, thank you.