Hey, great. We're back, everyone. Happy to have Spyre Therapeutics CEO Cameron Turtle and CMO Sheldon Sloan with us now. Maybe I'll kick it over to Cameron to kick things off with a quick overview of Spyre, and then we'll get into a Q&A. Cameron, over to you. Yeah, thanks so much for having us this morning, Alex. Maybe just to kick things off, Spyre is aiming to address what we see as the substantial unmet needs across a few baskets of autoimmune diseases, and our strategy is reflected in our two ongoing phase II trials. On the IBD side, we're combining optimized versions of antibodies against what we see as the best three targets in this disease area. That's α4β7, TL1A, and the p19 subunit of IL-23. Against each of these targets, we've engineered what we hope are improved versions of antibodies against these targets, and then we'll leverage the existing dose and exposure response relationships for each of these agents to hopefully target improved or optimized efficacy for each of them. We're combining each of these antibodies, these components, into three co-formulated combinations with an aim of blocking the orthogonal mechanisms of IBD pathogenesis with highly specific antibodies. It really gives us three shots at breaking what we see as the efficacy ceiling in this space and delivering a best-in-indication profile that combines greater efficacy, a nice safety, and then an improved dosing profile as well. Outside of IBD, we actually announced this morning the first dosing of our potentially best-in-class anti-TL1A antibody in a basket of three rheumatic diseases. We think targeting TL1A could be highly effective in these indications, as it has been in IBD, and that providing a quarterly or twice annual subcutaneous profile would be a leading product profile in these rheumatic diseases as well. Across these two studies, we think it's a really exciting time. Across these two studies, the platform and basket studies will be delivering nine proof-of-concept placebo-controlled readouts over the next couple of years, in indications that total over $60 billion in annual revenue. We think this approach is likely to potentially provide indication-leading profiles and provide substantial returns to both patients, physicians, and investors. Great. I think maybe starting with IBD, top of mind for folks, for you guys for right now, and we'll talk about rheumatologic diseases later. Sort of, you know, why is the field looking towards combinations here? We'll touch on other ways to potentially get to better efficacy, but you know, what's exciting about combinations? What has the field demonstrated in terms of clinical data that gets you excited about what you're doing at Spyre? Yeah, so maybe the background here is for the last few decades, we've been working on a range of different classes of therapies in IBD. Despite delivering more than a half dozen classes that have been proven in terms of delivering safety and efficacy in this space, we're still seeing that none of them provide long-term remission for the majority of patients and really helping patients get through the severe symptoms and complications of the disease. I don't think this is really a surprise given that this is a multifactorial disease. More than one pathway is involved in driving the disease in almost every patient, and blocking one pathway is pretty unlikely to stop it completely in most patients. A groundbreaking study in this space was J &J 's VEGA study. This was a compelling proof of concept that when you block multiple pathways at one time, you can deliver kind of substantially improved efficacy without apparent safety downsides. Specifically, J & J showed that combining their IL-23 inhibitor with a TNF inhibitor delivered nearly 50% clinical remission compared to approximately 25% on each of the individual therapies. I think the appropriate caveat to mention with the VEGA study is that it was a pretty narrow study. It was only looking at the combination in ulcerative colitis patients who've never been exposed to advanced therapies before. We kind of get this high confidence in this one narrow area, but it's a relatively small set. I think despite that, I think both the academics in this field and almost every sponsor in this space sees this as likely the future of IBD and kind of the most highly probable approach to breaking that efficacy ceiling that we have spoken about. I don't know if you want to call it a $60 billion question or whatever, but are we going to learn more about Duet this year? How is that study different than VEGA? Kind of how are you thinking about the read-through of that trial to what you're doing at Spyre? Yeah, I think on the back of that VEGA readout a few years ago from J& J, they launched three additional phase II studies, actually. They launched one in psoriatic arthritis called the AFFINITY study, which we'll talk about later. They launched two [Duet] studies, one in ulcerative colitis and Crohn's disease. Just briefly, we actually just saw the results from the Affinity study in psoriatic arthritis, which I think is incremental on top of VEGA first because it was looking, A, in a new population in psoriatic arthritis patients, and then it was also looking at a fully refractory population of all individuals who had failed a TNF inhibitor. Again, what they saw, looking at endpoints that now extended out four to six months, we saw that the combination meaningfully improved efficacy in that study. In my view, this is a very difficult population to see a benefit of a TNF combo in a group that had all failed TNF inhibitors. It was encouraging to see that incremental efficacy in that population as well. Now, the two Duet studies, I actually think it's somewhere between the VEGA and AFFINITY studies with a few new tweaks as well. In Duet, we're again looking at the combo compared to monotherapies and refractory UC and Crohn's patients. I think what we're most interested in seeing is does it continue to provide that incremental efficacy without seeing meaningful safety downsides. I think in general, our expectation is we're moving from a naive population in VEGA to a full refractory population. We expect all the numbers to come down. That's been seen in almost every study in IBD to date. Really what we're interested in seeing is how big does that delta stay now that we're looking in that refractory population and out for a year as well. I think it's also the first time we're going to see safety out for a year as well. I think that's also an unanswered question when we think about a TNF combo in this population. Obviously, the other big caveat here too is you're not studying a TNF as part of your combination. How should we think about interpreting these results in the context of the combos you're actually studying? Yeah, I think on the safety side, I would be hesitant to take any read-through that kind of a safety downside from a TNF-based inhibitor is likely to translate to our combinations. I think none of our agents have the individual warnings that come with the TNF, and I think that that's quite unlikely to be seen. On the efficacy side, I think it's a little bit more translatable, though I would still say it's a little bit tricky to know that, you know, is a TL1A very similar to a TNF or are there enough differences that that read-through is not possible. In any case, we think it's quite likely that our combos are superior to that combo. α4β7 has been proven superior to TNF in this population. I think most reasonable folks looking at the TL1A results compared to the TNF results would also say that TL1A is a superior class as well. I think almost regardless of what we see, we think our combinations are better positioned. Is there a specific delta you want to see between the combo and the mono, or is it much more, you know, overview, like a broad validation in your opinion, especially in UC? Crohn's obviously different. Yeah, I think Crohn's is a little bit harder. We have less direct benchmarks there. On the ulcerative colitis side, we've seen a number of studies in this space. I think what's been seen over the years in terms of what's a clinically meaningful delta on efficacy that has led to a meaningful change in practice is around a 10% delta overall. That's about what we saw in the Varsity study that led to Entyvio becoming kind of the number one product in this space. It's also about the delta we see of the P19 inhibitors beating STELARA as well. That delta is what I would hope to see in a phase three study of comparing any agents together. I think what we should all recognize as well is that the phase three study is very likely to be a mixed population, as in about a 50-50 mix of a naive population and a refractory. We got half the answer in VEGA. I think we're going to get the other half of the answer in the [Duet] studies. I think what we should all think about is, okay, what does this look like in a 50-50 mix? Do you see about that 10% delta overall? Obviously, the size of this market and the unmet need has not really been missed on anyone here. Beyond the combo work, there's a lot of small molecule bispecific development happening in this space as well. I guess how do you see that part of the competitive landscape shaking up? Yeah, so this is a topic that we spent a lot of time on when we were launching Spyre in terms of deciding whether we wanted to co-formulate our antibodies or make them as bispecifics. Obviously, we made a call here that we thought that the highest probability of success approach was to go forward with the co-formulations. The rationale for that is we think co-formulations are very likely to perform like the two antibodies together, and that's really what you're looking for in a combination. In contrast, I think there's really three specific challenges to bispecifics that we think co-formulations avoid. I think the first, and I think what has killed many bispecifics in the past, is an immunogenicity risk, that bispecifics are much more likely to link multiple targets together, kind of by their design, and form larger immune complexes that can lead to higher immunogenicity and a lack of functional activity of the antibody. In contrast, I actually think co-formulations may actually do the opposite. We see in the J& J study that when you co-administer the TNF and the IL-23, you actually see lower immunogenicity. We think that's possible with ours. The other two risks with or weaknesses of bispecifics is really the avidity of bispecifics is not always the same as what you get when you co-administer antibodies. I think we saw a really nice study that summarized this with J&J made a TNF IL-17 bispecific, and they found somewhere between 20 and 30-fold lower target engagement when those antibodies were formed as a bispecific than they did as monoclonal antibodies. I think that's a real risk. Lastly, kind of a necessary issue with bispecifics is they're a fixed ratio. They're either one-to-one in most cases or sometimes kind of two-to-one or others. I doubt that's right. I think we actually are knowing the dosing at this point of all three of our agents moving forward into the phase II study. None of them are one-to-one. I think it would be kind of, has to be quite lucky to end up that you end up with a one-to-one ratio. In general, we just think that the co-formulation approach is the highest probability of delivering the product profile we think. We also think we're ahead on this approach as well relative to the bispecifics in development. On small molecules, we just got the ECCO abstracts for MORF-057, and we also sort of have some top-line data from mirikizumab. Where do those fit in in your view? Yeah, I think it's a very interesting question. I mean, when we think about this market overall, I think when we test kind of orals versus long-acting injectables, we typically see that once you're out at a quarterly subcutaneous injection, that's preferred to even a once-daily oral if they have identical efficacy. I think identical efficacy is a pretty high bar for orals. I think the one example is potentially a co-formulation in terms of matching the IL-23, but I don't think we really have the large phase III data sets yet for this target, like we have in some other indications like psoriasis, where I would say it also doesn't quite match the biologics in terms of their efficacy. For the Morpho 5-7, as you said, we just saw the abstract go up for UEGW, and there I think it's very clear that it's not matching the efficacy of Entyvio. I think it broadly fits the premise that I think it's quite unlikely that orals will always match biologics in terms of their efficacy, and certainly I don't think they will match the efficacy of a combination of multiple optimized antibodies. Maybe pivoting back to what you're working on, you put out phase I data earlier this year for your TL1A assets. I guess maybe to sort of get to the end result here, what gives you confidence in moving forward two separate TL1A antibodies out of phase I? Yeah, Sheldon, maybe do you want to talk about the TL1A results and why we're taking two forward? Sure. We have SPY002 and SPY072. The 002 we're taking forward in our SKYLINE or IBD study, and the 072 we're taking forward in our [SKYWAY] or rheumatic disease studies. Each TL1A exceeded our product profile, and we're moving forward with both molecules in the phase II. Ultimately, the co-formulation ability of the SPY072 with SPY001 and SPY003 was slightly favorable, and the optionality that provides for future developing of combination regimens within IBD was why we picked the 002 for the IBD study. Yeah, I think one of the other questions coming out of the phase one was just, you know, what is this AE of chest tightness that you saw, and why are you confident this is not an overrecent signal? Yeah, a couple of things about the phase one study. We had, overall, the results were very compatible with any other healthy volunteer study. What we saw was a couple of instances within the first couple of hours of complaints of chest tightness, which patients had. The investigator nor the company felt this was critical enough to unblind the patient. We also have normal vital signs, normal EKG, and normal blood tests during these episodes. Neither the investigator nor the company felt that these were related to cardiac or pulmonary, and in fact, the patients are still blinded, so we didn't have the impetus to unblind the study either by the investigator at the phase one site or the company. Yeah. Moving on, your SKYLINE platform study is now underway. Maybe if you could talk about the design of the study and sort of why you made some decisions around IV dosing and induction, and then sort of the maintenance regimen as well. I'm going to take that. The SKYLINE study, a key advantage of this is that we have our three monotherapies in a single portfolio, so we can conduct a blinded study that looks at all our therapies and combinations on the same dosing schedule. This will avoid bias, and we have an accurate view of which agent or agents are most effective and safe to move to phase three. I would just say we're incredibly excited on the initiation of this platform study, so we're already enrolling patients, activating sites across multiple geographies. Yeah. As I mentioned, this is a platform trial investigating our three monotherapies. Part A is open-label of all our monotherapies, with each being added to the study after the interim phase results. Yeah. The objective for Part A is to demonstrate early proof of concept for our three monotherapies, with each expected next year in 2026. Once we finish enrolling the Part A, we seamlessly go on to Part B, which is placebo-controlled and evaluates all our monotherapies and combinations. Study design was developed with the goal of identifying the optimal products to advance to phase three. Now, it could be one or more while fulfilling the contribution of components for combinations. We're also exploring dose ranging for each of our monotherapies. The single phase two study provides six shots on goal, Cameron already mentioned, reading out together in 2027. Our goal is to deliver a best in indication product profile with superior efficacy and best in indication quarterly or twice annual dosing that could also transform the treatment paradigm in IBD. If you look at why we're giving subcutaneous IV induction versus subcutaneous induction, the SPY001 and SPY002 molecules, we feel very confidently could be delivered subcutaneously for induction and maintenance if we were to move them forward as monotherapies. However, our expectation for the SPY003, which is our anti-IL-23 P19 antibody, is that higher doses may be required during the induction phase, which has been observed for risankizumab, where there's a suggestion of higher exposures leading to greater efficacy with the class. Yeah. SPY003 requires higher dosing. We're planning the study to pursue IV loading and induction for all our monotherapy and combination arms in order to keep the blind with subcutaneous maintenance dosing. We'll assess our phase III subcutaneous induction feasibility for all three monotherapies based on these results. Maybe with the open-label data next year, what do you view as a good result here? I think part of the thesis for OL-1 too is exploring this potential for exposure response. For TL1A, what's the comp here and how confident are you in the actual dose selection there? Yeah, I think I'll take this one. In general, the data from Part A, really what we're looking for and what we and others should focus on is the objective measures of disease improvement. It's an open-label study, so things like endoscopy and histology should be the primary focus. The histological index that we're using has been used in a few studies, and those are probably the best benchmarks. We've seen it in the [MorPhic] study in an open-label context, and it was also used in the VARSITY study. It really gives us three benchmarks to look at in terms of things that you would expect to see in an open-label study. Of course, we're going to be measuring the typical UC endpoints, like clinical remission that we'll see in the study, and I'm sure that will be of interest as well. In general for us, what we're looking for for each of these in terms of our overall strategy is at least matching the first-in-class agents on these targets. We don't need to see that they meaningfully improve on efficacy on a monotherapy perspective because we think the combinations are likely to provide a step change in efficacy relative to the first-generation molecules. We think we could see optimized efficacy in terms of slight improvements, but the probability that we see a doubling of efficacy is much more likely to come from the combos than it is from increased dosing with each of the monotherapies. Yeah, do you want to, I want to skip over to SKYWAY because I want to spend a little bit of time here. You know, TL1A and rheumatologic disorders, you're now leading the pack here. What was the data, I guess, what was the rationale for starting this trial? Yeah, so I mean, we spent the first couple of years of Spyre deciding where else to take TL1A. We thought we were working on a better molecule with our TL1As than the first-generation molecules, meaningful improvements in potency, half-life, bioavailability, formulation than the first-generation molecules overall. We thought, you know, this is probably worth taking into multiple indications if we have that product profile. We spent a couple of years deciding what we thought were the most attractive indications. The ones that we came up with are the ones that I think overlap quite substantially with the pathogenesis that we see in IBD in terms of TH1, TH17-driven diseases, where the proof of concept for TL1A is most translatable. In these rheumatic diseases, in addition to that mechanistic overlap, we also see substantial amounts of human genetic evidence, human tissue evidence, and animal studies as well that support that TL1A could be a highly effective agent in these indications. Beyond just kind of biology and clinical probability of success, we also like these indications because our ability to get these studies done in a relatively short order is probable. We think we can start this study dosing, you know, today, and then we expect to have the results from each of these indications next year. Really rapid proof of concept in these indications. Usually that's also a pretty good indication of what else we like about it, which is that there's substantial unmet need in these markets and there's substantial commercial markets at the end. We think, you know, if we come out with a highly effective agent that doesn't have the safety risks of many products in these indications and is dosed on a quarterly or twice annual basis, I think this could be a leading product in these areas. In terms of cadence of data catalyst next year, any sense of whether or not we should expect, you know, some of the rheumatic disease data before the open-label UC data, or is that still not clear at this point? I think it's going to be, it's hard to know right now. We're getting both of these studies off the ground. I think both are kind of getting approved in multiple geographies as we speak and dosing across each of them. We're going to have six readouts next year that are somewhat independent of each other in terms of the open-label readouts from the Skyline study and then these placebo-controlled readouts in SKYLINE. We'll have a better sense of timing in a few months from now as we get to see these sites activate and start to see the enrollment rate across them. Besides our six, there's actually going to be other TL1A readouts next year, we think as well. I think overall will help us understand the total addressable market for TL1A. It's quite likely that we'll see the Merck SSCILD readout next year. It's possible that we could see some of the dermatologic readouts that Merck or Roche have announced as well, which are also large indications that tend to enroll quickly. As a reminder, Merck is running a study in HS and Roche is running a study in atopic dermatitis. We think those could enroll quite quickly and we could see those results quite soon as well too. Because you're not doing enough, I guess, do you see yourself moving SPY072 forward or is this something that you'd want to partner? What does the future of Spyre look like next year if in fact you see clear data for rheumatic diseases? I think the future here looks pretty exciting across the board. I think in general, we've been opportunistic and aggressive from a capital formation perspective over the first couple of years here to really provide the funding to do everything that we're doing in parallel. I think so far our execution has proven that we can do things on the timeline that we say. With the capital that we've raised, we will release nine placebo-controlled readouts plus three open-label ones over the next two years that are fully funded today with a year of cash beyond that. We're certainly not funded to run all the potential phase threes on the back of it. I do believe that the commercial markets on the far side of this would justify the investment in phase threes if we have the product profiles that we could, which is potentially additive combination efficacy in IBD and a novel mechanism in the rheumatic diseases that's dosed on a product, on a dosing convenience that's superior to anything else on the market. In terms of how we proceed to prosecute these things forward, I think we'll be excited about pursuing as much as we can ourselves. I think that's where we could capture the most value, but it's not lost on us that there's substantial commercial interest in these from a variety of strategic players. I think we'll have multiple options on the table as we get to the second half of next year. Obviously we've talked about the AFFINITY data in psoriatic arthritis earlier. Is there a path for combinations in rheumatologic disorders as well? Yeah, I think what we would need to see to advance in terms of combination therapies in these diseases is seeing that TL1A is effective, at least as effective as what we see from other monotherapies in the space. If it is, I do think that combination therapy is quite likely to address the unmet need in many of these hard-to-treat rheumatic diseases as well. It's not unlike IBD in that these are complex diseases, heterogeneous diseases that are both different in different patients. Within one patient, it's not one mechanism driving their disease completely. I think really these co-formulations of highly targeted antibodies are a pretty ideal approach for that, where you don't have the off-target effects of some broader mechanisms, and you can block really orthogonal mechanisms and potentially get additive efficacy in these tough-to-treat diseases. From a cash flow and rate perspective, can you talk about where that gets you and what's included in those assumptions? Yeah, just the background here is we have $527 million on the balance sheet as of the last quarter, and that takes us into the second half of 2028. We expect all of these readouts from the SKYLINE and SKYWAY studies in 2026 and 2027. We have a year of cash beyond all of these readouts. We really think that both of these studies are likely to provide a number of products that would justify moving forward to phase III. Great. Cameron, Sheldon, I appreciate you taking the time. Thanks. Thanks, Alex.