Great. Hello, everyone, and welcome back. We now have Spyre Therapeutics CEO, Cameron Turtle, here for a fireside chat. Cameron, maybe I'll kick it over to you for a quick company overview, and then I'll jump into a Q&A. So Cameron, over to you. Sounds good, and thanks, Alex, and thanks for having us. So the background for Spyre here is that we are predominantly focused on inflammatory bowel disease, or IBD. It's a disease that affects about 2.4 million Americans, and despite being a very large set of individuals, I would say there's still quite a bit of unmet need in this space. There are a handful of approved agents in this space, though they typically hit a therapeutic ceiling in around 25% placebo-adjusted remission rate. So patients are often forced to cycle through multiple therapies to get into sustained remission. And then also, the product profiles in this space are maybe a bit lacking relative to some of the other large I&I categories, where we still have drugs on the market that are dosed every two to four weeks, still IVs on the market today. And really, at Spyre, we're hoping to improve on both of those things simultaneously. So we're making extended half-life antibodies against what we think are the best targets in this space, that we hope can improve the dosing intervals to get out to at least every eight-week dosing, if not quarterly dosing, which we think would be a major step up relative to most products in this space. And then, at the same time, for both the design of the antibodies themselves, and I'm sure we'll talk today about the possibility of testing these as combinations as well, we think there are multiple ways to potentially improve on that 25% therapeutic ceiling that we see in this space. And so really improving both of those together, we think, would be a meaningful step forward for IBD patients. Yeah, agreed. And you talked about the unmet need there, this therapeutic ceiling, but I think one of the other interesting points here in this space is just the success of Entyvio as a biologic therapy. You know, despite some, you know, product profile elements that may not be ideal. Can you talk a little bit about why Entyvio has been such a you know a successful drug in this space? Yeah, so, so I think one of the important things to know about IBD is it tends to be a, a disease that's diagnosed quite early in life. So these, these tend to be individuals even diagnosed in, in childhood or adolescence, and continue to have a chronic disease through most of their working years. And as a result, one of the priorities for therapeutics in this space is really on the safety side. Compared to most other I&I categories, it is something that we really do prioritize the safety of agents. And Takeda's Entyvio is the one of the leading products in this space because its safety is very clean. Targeting alpha-4 beta-7, this heterodimeric integrin is a specifically unique target in that it blocks the trafficking of immune cells into the gut specifically. So it is not a broad immunosuppressive class that is suppressing the immune system throughout the body. It is really directed to the inflamed gut, where IBD is impacting these patients. And that means you don't have the infection risk and the malignancy risk that you have with other classes, and leads to physicians and patients feeling more comfortable being on this drug for extended periods of time. It's why this is where we started with our portfolio here, and really moving forward with a long-acting version of it is something that we feel quite comfortable going to a long-acting version because of that safety. If there was an acute safety concern with hitting this target, we would be less excited about moving forward with a quarterly version of that target. Yeah, and before we get to SPY001, I guess, you know, with Entyvio as kind of that leader or standard of care, like, how is the market, you know, evolving over the sort of short to medium term in your- Yeah, so I think it's a huge class, right? And this is a $20 billion-plus category. There's plenty of competition in this space. Say, new agents that are either in development or kind of entering the market here. And really, well, I think we're hoping and wondering if any can break through that therapeutic ceiling on their own. I would say the challenge is most monotherapies have been unable to do that without concomitant safety concerns. So some of the broader immunosuppressive classes, say the JAKs, for example, yes, they are able to drive greater efficacy, but at the same time, they carry safety risks that are not the same as Entyvio. So I think that is the question, is can another monotherapy get there? We'll see. What I think has definitively broken the efficacy ceiling was J&J's VEGA study, which was a study that tested two advanced biologics in combination together, a TNF and an IL-23, and they showed a 47% adjusted clinical remission rate, almost doubling the efficacy there. And I really think that over the next few years, this is likely to be the direction that this field evolves, and we see most of the other players in this space acting with that in mind, that the combination of targeted therapies is likely to be one of the few things that can drive that efficacy advantage without causing the safety concerns that you get with some of the very broad immunosuppressive classes. Great, that's helpful. And I did wanna, so let's talk about SPY001 now, and how the design of this molecule, you know, is based off of vedolizumab and sort of the broader product profile that you're hoping to achieve. Yeah. So yes, sir, so again, we started with Entyvio. We think this is a really great drug to start with. We think that the way that they've designed it to bind to the interface of this heterodimer makes great sense for the potency and selectivity of it. And for SPY001, that's what we focus to match with Entyvio, so we're targeting the same epitope as Entyvio is, with, we think, very, very similar potency and selectivity compared to vedolizumab. We really are not trying to test or define new biology here relative to vedolizumab. What we are trying to improve with vedo is a couple things. One is, can we improve the convenience of this product? It's currently dosed as a every two weeks subcutaneous injection or an IV infusion every eight weeks, neither of which is a profile that patients or physicians feel is optimal, so what we're hoping to do is incorporate a half-life extending modification. A YTE substitution is the modification that was made here, when we've showed in preclinical animal studies that it has approximately tripled the half-life of vedolizumab by incorporating that mutation. Yeah. The second thing that we plan to do is dose it differently as well. So we plan to use a high-concentration subcutaneous format. The combination of increasing the dose relative to the subcutaneous version of vedo and meaningfully extending the half-life, we think will allow us to test kind of a much longer dosing interval and improve that- Yeah ... which we think is one of the weaker aspects of the product profile. ... Yeah, and I do want to get to, you know, kind of this translation from the preclinical work that you've done, and then you're going to have your first phase I readout later this year in humans. And so can you walk us through really sort of the benefit of the YTE modifications here, and how we should think about translating the non-human primate half-life data that you mentioned to humans based on the clinical experience to date with the YTEs? Yeah. So I think that one of the nice things about the YTE is that. I think at this point, it has been quite de-risked in terms of its ability to extend the half-life of antibodies. I would say it's not always the case that you can just put a YTE onto an antibody and get a meaningful half-life extension, but I think with reasonable and kind of appropriate antibody engineering, you can often lead to a doubling to quadrupling of the half-life of a wild-type antibody with this YTE substitution. It increases binding to FcRn and causes the antibody to be recycled instead of degraded. I think what we're particularly interested in for this alpha-4 target, we know alpha-4 beta-7 is a cell membrane-bound target. What you can see for antibodies that bind to targets that are cell-bound is that you can see target-mediated drug disposition- Yep ... meaning the cells that you bind to actually internalise and degrade the antibodies. And so we think that kind of as we're moving this molecule into the clinic here, we'll see it to kind of what level of half-life extension do we get relative to the 25-day half-life that vedolizumab sees in humans. Yeah. And I guess based on some of your more recent non-human primate data, you know, based on some of your modeling, why, I guess, why wouldn't you get to every 12-week maintenance dosing? Yeah. So vedolizumab's dosed every two weeks. So we think we're planning to increase the dose in our subcutaneous format. They dose a little over one hundred milligrams in their subcutaneous version. We think we'll be able to dose more than three hundred milligrams in a standard auto-injector. So in one way, we're just kind of increasing the dose of a very well-tolerated molecule. And then, depending on the half-life extension we see, we think that will determine what our dosing interval is. And so I think we've put out some bars for what we think would be success. We think with a 35-day half-life, so a pretty modest improvement going from 25 to 35 days, we think we would be able to dose this molecule Q eight weeks. Yeah. Which we think would make it the most convenient product in this space. As an auto-injector, Q 8 weeks, there are not auto-injectors Q 8 weeks yet in this space, only on-body devices. And then on, we think if we get to a 40-day half-life, we think we would be able to dose at Q 12 weeks. Again, with what we've seen in NHPs, we think this is a pretty good bet. But of course, there's always error bars when you translate into the clinic, and I think we'll see in the next few months here if we were able to achieve that half-life extension. Yep. And I guess, you know, maybe putting the specific PK data for vedolizumab in mind here, and the specific target that you're thinking about, like, why isn't the experience from Apogee directly translatable to Spyre in this context? Yeah, I think it is the target, right? Every target is different, every indication is different. So again, alpha-4 is a cell-bound target, so we think it will likely have more TMDD than other targets that are soluble. So that will, we think, limit the half-life. Within our portfolio, we think actually it probably is likely to have the shortest half-life of our three programs. Alpha-4 beta-7 is cell-bound, TL1A is sometimes soluble, sometimes cell-bound, and IL-23 is always soluble. So we would expect that alpha-4 actually has the shortest half-life and the most frequent dosing interval of our three. I think it's why this readout, in particular, probably matters most within our portfolio because it will define not just the dosing for our alpha-4 beta-7 program, but we think it's likely to limit the dosing of the entire portfolio as we get into combos. Yeah. And if we can show that we can dose Q 8 weeks or even Q 12 weeks with the alpha-4, I think it's quite likely we'll be able to do that with the TL1As and the IL-23 as well, and I think that sets up, I think, the only company that has the ability to dose combos on a Q 8 to Q 12-week basis. I think that really would be an exciting profile for the overall pipeline. The other wrinkle here with alpha-4 beta-7 is the phase III data suggesting that potentially higher exposure could drive higher efficacy. Can you talk about how you're going to be able to test that, potentially- Yeah ... what we will learn from the phase I? Yeah, so just to provide the background here is that with vedolizumab, both in their phase III data, as well as in multiple publications looking at real-world data in the clinical setting, what has been shown with vedolizumab is that individuals that have higher exposures, individuals that have more drug on board, tend to have a higher probability of clinical remission. I think that relationship is strongest in the induction setting, as in, when patients are in this acute inflammatory phase, it seems to be that they need quite a bit of drug on board to lead to clinical remission. That relationship is weaker, but still exists in maintenance, where it seems like more drug on board could be helpful for patients here. And on the other side of it, we again know the safety of this molecule is very, very well tolerated, where Takeda actually tested much higher doses. Commercial dose is 300 milligrams. They've dosed up to 750 milligrams, and it's been well tolerated. So we do expect, and this is a phase I study in healthy. We won't be looking at efficacy here, but we do think our phase I data will allow us to project what our phase II dosing is likely to look like, what we expect the distribution of our concentrations of the antibody will be, and we can relate that to what levels of efficacy are seen with Takeda's molecule at those different levels of exposure. So I think that our phase I data should be informative, though, of course, not looking directly at kind of clinical remission in healthy volunteers. Just sort of wrapping up on the phase I update, you know, can you talk about timing of the update, and then also, what do you expect to be able to share with us that sort of gets at kind of some of those key points around exposure and then also half-life? ... Yeah, so we started dosing the study back in June, so we're kind of a few months into dosing the healthy individuals and escalating through cohorts now. We still expect and plan to have data released by the end of the year this year. And we expect that will be, say, a mature data set from the first few cohorts here, where we'll be able to show kind of the level of exposure that is achieved with the molecule, as well as a reasonable estimate of the half-life, which I think is probably the number that's going to matter most and determine whether or not this is a Q8 or Q12-week drug. Of course, safety, immunogenicity, some PD measures are also interesting, but if I were to say what should be the focus and what is our focus, is that can this molecule be delivered on a quarterly basis? I think that would be a major victory here if we achieve that. Great. And shifting gears to 002, your TL1A compound, obviously lots of interest, but maybe taking a step back, you know, why is this such a unique and interesting target for IBD? And- Yeah, so I think, starting from the more recent data, is that as a monotherapy, TL1A has some of the most impressive clinical remission rates as a single agent in this space, without the apparent safety effects of some other classes as well. That said, we only have phase II data sets at this point, so it could be the case that as we get into larger studies, we see other things. But I think at this point, it is one of the most attractive monotherapies in this space. I think beyond IBD, it's also an interesting target. There are more than a dozen different indications where TL1A is implicated, either by genetic information, or patient samples from various diseases, or animal studies demonstrating that anti-TL1A can benefit various different indications. I think that leads to the additional excitement around this target, that it could become a pipeline and a product, as you've seen in some other I&I classes as well. I think that's why we are very excited about a molecule here, and really, we started working on this thinking, "Hey, these first molecules look exciting. The proof of concept clinical data is very attractive," but we think there were properties of those molecules that could be substantially improved, and that's what we're moving forward with our Spyre program. Yeah, and what does it... I guess at this point, what does it mean to be the best-in-class TL1A? Yeah. So I think, again, we only have phase II data sets. So it's not the case that we have kind of these well-rounded phase III and commercial data sets that we just talked about for vedolizumab. That said, we can look at the antibody properties, and all the antibodies that we have come from an antibody engineering organization that have made dozens of antibodies over the last few years, and we look at the properties of the antibodies that are ahead of us against TL1A and think, "Hey, that's not what we would pick if we had a wide range of antibodies. Those are not the properties that we would select for," and so in particular, I think we see antibodies ahead of us that have relatively poor potency, in some cases, can be a log-fold lower potency than you would expect for an industry-grade antibody. We see antibodies that have high rates of ADAs and immunogenicity, that can't be formulated at a high concentration as well, or have developability issues as well, and really things that we think you can improve all in one package. Also, that don't incorporate the half-life extending modifications, so are dosed on a pretty frequent basis as well. So really, the intention with this program is, "Hey, let's just make the best antibodies we can against this target." We pretty sure that this target works well in IBD at this point, in UC, and likely in Crohn's as well, and I think we'll see over the next few years where else it works, and I think we have molecules with substantially improved properties that we can follow into the indications that we think are most promising. Yeah, I guess to that point with, you know, adding a YTE and the questions around what it makes to be a best-in-class TL1A, as you're looking at some of the earlier stage competitors out there, also looking to develop half-life extended antibodies, you know, what are your key questions as it relates to, you know, how they might compete with your compound? Like, what else goes into developing a best-in-class antibody beyond just a YTE? Yeah. So I think for targets that don't have acute safety issues, I do think extending the half-life makes a lot of sense, to just target a more convenient product profile. However, beyond that, that is one of the few, one of a long list of things that we're looking at, for antibody properties, and I mentioned a handful of them. Potency and selectivity is kind of the critical features to be at least as potent, if not more potent than the other inhibitors against those targets. And then, we don't talk about it as much publicly, but the developability of these agents is critical as well. The stability and concentratability of these molecules is really important to us, so that we can make high-titer cell lines, and ultimately have low cost of goods agents that we can deliver at high concentration subq formats. We only usually present a single molecule per program, or in the TL1A case, we're doing two, but that is the result of often dozens of molecules that we make all originally, and sometimes put even a dozen plus into non-human primates as well. It's not the case that you can just slap a YTE on any antibody and end up doubling to quadrupling the half-life. Mm. There's multiple examples of agents that have been made, where they add a YTE or a half-life extending modification and end up in the similar range of half-life as the wild type ones. So again, there, there's a lot that goes into antibody selection. We're only showing the good ones. Yep. No, totally makes sense. What is- what's the current status of 002? Any timelines there? Yeah, so we are done tox with both of the two TL1A molecules, the IND-enabling tox. We had the top dose was our no observed adverse effect level for each of them, which is great news at this point. We will be dosing both of those molecules in healthy volunteers before the end of the year as well, and expecting to releasing kind of a similar phase I data set from our TL1As in the first half of next. Still everything on track there. Expect us to start dosing here in the next couple of months. And then for 003, I think the high-level question here is, why develop your own IL-23? ... Yeah, so I think the answer here is that, look, the IL-23s are already Q8-week drugs on the market today. That's a pretty convenient product profile already. I think as a monotherapy in IBD, I don't think we would be as excited about bringing forward an additional IL-23. That said, if we could make it quarterly or every six months, I still think that could be an interesting agent. But the real reason we're making an IL-23 is we think it's a very good combination target. Besides alpha-4 beta-7, IL-23 is an extraordinarily well-tolerated class, and we think in terms of probability of a safe combination. I think it's hard to say—think of anything that's higher probability of a safe combination than alpha-4 beta-7 and IL-23, with, I think, a strong belief that there's an opportunity for efficacy advantage of those two targets as well, with very orthogonal biology. Yeah ... and evidence published for those agents working either additively or synergistically as well. So I think that's really the reason here, is we think it could be a great combination agent with either the TL1A or the alpha-4, beta-7. Yeah, and before we get into sort of combinations, I have a question from the audience around whether you think you can break through the therapeutic ceiling through this broader genetic profiling approach that we saw with TL1As- Yeah. ... and then better patient selection. How are you applying that, I guess, broadly outside of TL1A, but also in alpha-4, beta-7, et cetera? Yeah, so I think that was one of the more exciting findings over the last five years in I&I, seeing both Prometheus and Telavant at the time demonstrating that they could show, with pretty simple genetic selection tool, an improvement in remission rates. And I think that is kind of leading to the hope here that we're approaching an era of precision medicine in I&I as well, which we've seen be incredibly powerful in Mendelian diseases and oncology, but really not in some of the broader categories like I&I. So our approach here, we think we can build on what was successful with these two other agents against TL1A. They looked at just a handful of SNPs, a handful of genetic modifications to select individuals. We're working with one of the largest IBD biobanks to define what we hope will be a more powerful patient selection strategy, looking at a broader set of either genetic and/or proteomic measures. We'll test those in phase two and see if we can extend or replicate or improve upon the level of improvement that was seen with those first-generation TL1As and first-generation selection strategies. Great. And getting into the combos, you know, we talked about the VEGA study, but I think one of the other questions that I get, I'm sure you get a lot, is: Why is combo, you know, maybe making more sense than a bispecific strategy? Yeah. So I think... I mean, I think that they're kind of moving in the similar direction, which is, how do we get hitting two specific targets in a single product? and I think that is a really critical feature here so that you're not developing separate products, needing to get multiple things approved. That is really what has limited the use of combinations today, multiple branded products. So it's how do we get a single shot that does two things at once? Bispecifics can do that, co-formulations of antibodies can do that as well. We lean towards the co-formulations being an approach that is more likely to have an optimized safety-efficacy relationship than a bispecific, because you can tune the relative amount of each of those in a co-formulation. We can decide that we need one hundred and fifty milligrams of one agent and two hundred of the other, or vice versa, and we can adjust based on the information that we get. With a bispecific, you have a fixed agent with fixed affinities. You can only dose up and down that affinity. It's highly likely that you're hitting one target more than the other, and maybe one too hard, one too little, and you have less flexibility there. The other challenge is some of the antibody engineering, and certainty around it does not seem to hold for bispecifics as it does for monoclonals as well. We have just not seen bispecifics that get to the same level of half-life, as monoclonals with half-life extension. They're much shorter dosing intervals for bispecific so far. Don't think we have a great explanation for that yet, but that seems to be the case, that we haven't seen bispecifics that get there. And then lastly, for alpha-4 beta-7 in particular, it would be a challenging target to decide to make a bispecific for, because it is a cell-bound target that you're binding to predominantly in the periphery, whereas the cytokines that we're targeting, TL1A and IL-23, those are predominantly in the inflamed tissue itself that you're trying to bind to. So it is. It may be not possible for a single antibody to hit both of those, and even if it were, I'm not sure you would want to bring these, these, these cytokines into direct proximity with the immune cell types that you're trying to prevent from being active. I think in our case in particular, a bispecific for two of our three combinations really does not make a ton of sense. Yeah. And then in terms of what are the next steps, I think the phase I data. It's really clear, like, what you want to see from a PK/PD perspective. And then you talk about multiple clinical readouts by 2027. You know, what does that look like to get to reasonable proof of concepts over the next couple of years across these programs? Yeah, I mean, I see the next year for Spyre basically proving that these building blocks are what we think they are, that we can have quarterly versions of each of these agents and demonstrate that these are the targets that we think are the best, and hopefully we'll show that in our phase I studies. At the same time, we'll see the VEGA readout come from J&J, which is looking at their TNF IL-23 combo in both UC and Crohn's patients, in patients that are biologically experienced. And I think those readouts are going to be very defining in terms of what the future of this field looks like. And then we expect to run a phase II study that incorporates both our monotherapies and our combinations. And I think uniquely here, if we show what we hope to in our phase one studies, we'll be pursuing a product profile that no one else is targeting: quarterly combos, single shots every quarter. I think you're seeing a lot of messier combo studies, where people are combining Q4 weeks, Q2 weeks, Q8 weeks, subQs, orals, IVs. I think we have the opportunity to have a very elegant combo of a single quarterly shot of a co-formulated antibody. I think if the future is combos, which we believe is quite likely here, I think we're pretty uniquely positioned in that market. Is it fair to say you might be in a position to share more details around the phase II design with, with data later this year? I think we will be taking our phase I data, talking with all the regulators about it as well, and then I expect we'll be announcing phase II study as we get into the first half of next year, not, I would expect, kind of as we're releasing each of the phase I datasets. Great. And then I guess, I talked about 2027, but I guess when you talk about cash runway, what are the embedded assumptions there, moving forward? Yeah, so we're expecting, of course, to read out all of these phase I studies, and then frankly, have pre-funded a major portion of these phase two program as well with the cash on hand. So we expect that we'll have multiple catalysts, as well as launching the phase II study we described, with the cash that we have on hand today. Great. Well, Cameron, always fun to chat. I appreciate you joining us today. Cheers. Thanks, Alex.