My name is Yatin Suneja. I am one of the biotech analysts here at Guggenheim. Welcome to our inaugural Healthcare Innovation Conference. It's my pleasure to introduce our next presenting company, Spyre. From the company, we have the Chief Executive Officer, Cameron Turtle. Cameron, why don't you maybe give a five-minute update on the company? Obviously, some very exciting data that were presented a couple of days ago. Put that data in context, and what are some of the upcoming milestones, and then we'll go into sort of a Q&A. Yeah, that sounds good, and thanks for having me. Thanks, everyone, for attending. So the goal at Spyre is to develop what we hope to be: a next generation of products for inflammatory bowel disease. And what we see as the unmet need in IBD is a mix of efficacy, where most active agents in IBD cap out on efficacy at a therapeutic ceiling of approximately 25% clinical remission rates, as well as product profiles that, for a market of this size in the $20 billion-$30 billion range, the product profiles are kind of less than what you see in other I&I indications, where drugs are still dosed every two to four weeks in many cases. Still some IVs on the market as well. And so our goal with Spyre is to hopefully fix those simultaneously or improve upon those simultaneously, and we're aiming to do that by engineering what we hope are a next generation of antibodies that incorporate half-life extending modifications that we believe will enable extended dosing that will take us to at least quarterly dosing, so four shots a year, which we think will be a substantially improved convenience profile. And then we intend to or aim to improve efficacy with two approaches. First is optimizing the dosing of each of these targets. We think there may be opportunities to derive greater benefit with different levels of coverage of each of these targets compared to previous molecules in the space. And then, I think most excitingly and ambitiously is testing these agents together in combination, which we have proof of concept in IBD has the potential to dramatically increase efficacy and break through that decades-old efficacy ceiling, and we intend to test that with our agents on this unified quarterly basis, move forward with quarterly combinations, which we think is a target profile that no one else in this space can approach. Very good. So how did you come up with these three targets? So you have chosen alpha-4 beta-7, then you have a new emerging target, which is TL1A, fairly de-risked but not yet sort of commercial, and IL-23. How are you using this? What is the goal eventually with these three targets? Yeah, so we started in terms of determining which agents to pursue by looking across the agents that had achieved at least proof of concept in IBD and picked those that had efficacy in this range of the therapeutic ceiling across ulcerative colitis and Crohn's disease, but then did not carry the same safety risks that we see with other classes. So none of these three agents carry black box warnings, nor do they have safety monitoring requirements that you see with other approved classes in IBD. And this kind of safety profile is critical for both of the strategies that I described in terms of longer half-lives, and if you don't have a safe product, you may be worried about extending the dosing interval. In this case, we're not. It also enables us to test higher doses for potentially greater efficacy with these classes. And then when you think about combinations, safety really is paramount that you're not getting additive immunosuppressive risk between multiple classes. And we think in particular, alpha-4 beta-7, which is a gut-selective mechanism, it does not carry the same broad immunosuppressive risk that other classes do in this space, and we think that should lower the risk of combination safety concerns when we move these agents together. Got it. What is driving this sort of rush toward combination therapy? What have we seen, if you can put that in perspective, at least from the competitor standpoint? And then we'll just discuss these three molecules in more detail. Yeah, so the proof of concept for combinations in IBD is driven by the Vega result, which is a study that J&J reported almost exactly two years ago now, where they tested their anti-TNF and anti-IL-23 agents together, and they showed in the monotherapy arms 24% and 25% clinical remission rates, and then a 47% clinical remission rate in the combination arm, so nearly doubled the activity in the combination arm versus the monotherapies, really just a completely different level of efficacy than anything that we've seen in this space, and I highlight Vega as the most definitive randomized study, but it really is building off kind of a lot of experience in this space of physicians using combinations in their clinical practice. It's building off animal studies that suggest there might be additive or synergistic activity, as well as human genetic evidence that this is certainly a multifactorial disease where multiple pathways are contributing to disease pathogenesis. I think it's logical to then believe that inhibiting multiple mechanisms could have additive benefit from an efficacy perspective. Got it. So let's drill down on SPY001. You presented data earlier this week, very significant improvement in half-life, and it also seems like from an exposure perspective. What led to that, and then what were some of your key findings from that study? Yeah, so just as a reminder, our Spy1 program is our first program targeting Alpha-4 Beta-7, same target as Vedolizumab. And we really aren't aiming to test meaningfully different biology here. We're targeting the same epitope as Vedolizumab does, and we have very similar potency and selectivity in our preclinical studies. What is meaningfully different between Spy1 and Vedolizumab is its half-life, which is accomplished using the YTE substitution that increases recycling of the antibody. And in preclinical studies, we saw that it had approximately triple the half-life in both non-human primates as well as a mouse model. So we took that into a phase one study that started earlier this year and just reported data this week showing that we even exceeded our expectations with what that molecule could do. We saw a half-life of over 90 days in our lowest cohort, over 100 days in the second cohort. And we believe that this is a molecule that we had thought it could be an every other month or quarterly dose drug. Now I think we're quite confident that this drug can be dosed quarterly, and probably it can be dosed on a twice-annual basis as well to accomplish the same level of exposures that Vedolizumab had. So I think as excited as we could be by the data, and it's clean on most other properties as well. So safety looked unremarkable, which is exactly what you want in a Phase I study, and also show complete saturation of the target here, which is alpha-4 beta-7 over all the time points we had. Got it. Can you talk a little bit about the exposure also, because I think that's another point that you were trying to make is that if you are in that certain quartiles, you might drive a little bit better benefit? That's right. So the background here is that Vedolizumab, they explored, they showed an exposure response in both the pivotal studies, the Gemini studies for Vedolizumab, and then also in the real-world setting, this has been evaluated as well, looking at clinical remission rates for patients with different levels of Vedolizumab on board, and in both of those settings, the clinical trial setting and the real world, the relationship that's seen is that patients that have higher exposures of Vedolizumab have a much higher probability of achieving clinical remission, so this is something that was highlighted in the BLA for Vedolizumab with a comment that maybe higher doses should be explored to potentially improve efficacy here, and that's something that we intend to do with Spy1. We believe we've seen that Vedolizumab is very well tolerated, up to two and a half fold the dose it's been tested, and it is safe. And so we intend with Spy1 to test a higher dose than is seen with Vedolizumab to cover the target to a greater extent in the induction setting and see if we can achieve greater efficacy with this agent as well. Got it. What about the concentration? How is that relative to Entyvio dose? Yeah, so Vedolizumab doses, and when we plan to as well, loading doses in the IV setting and then switching to subcutaneous in maintenance. That's how we plan to dose ours as well. I think we've shown in our updated slides as of yesterday our coverage of the target where, of course, Vedolizumab has 25% of its patients in the fourth quartile of exposure, the definition of the quartile there, and the dosing that we propose and project to get the vast majority, if not all, patients into that fourth quartile of exposure where Vedolizumab has its greatest efficacy. Got it. I think the one question that we have gotten from some investors is on the immunogenicity. How comfortable you are with the immunogenicity profile of not just the target of the technology and what we should expect from you, because that data was not sort of shared or analyzed? That's right. Yeah, so we don't have the ADA data yet from the Phase I study. We will have it, and we'll present it at an upcoming medical meeting, so that we will share that soon enough. The background is that there have been multiple head-to-head studies between YTE and wild-type versions of antibodies that have not seen a difference in immunogenicity profile, and it's certainly true that across the range of extended half-life antibodies that have been developed, there has not been a class effect of these agents having a greater immunogenicity risk. We're pretty sure that the impact is likely to be low with Spy1, given that we saw kind of meaningfully extended half-lives and consistent PK in the study, which ADAs can have an impact on pharmacokinetics, and they also can have an impact on pharmacodynamics, and again, we saw complete engagement of the target. So we think it's quite likely that the immunogenicity here is not impacted, but we'll be exploring that in the upcoming months, and we'll show you more. Then in terms of then for you to test the dosing, it enables you to do six-month, every six-month dosing in maintenance, but I think you're still evaluating quarterly once. That's right. So the precedent in this space is typically doing maintenance dose ranging in the pivotal Phase III studies. So our expectation, as we showed in the last couple of days, is to run a Phase II study where we explore not just the single agent, but Spy1 as well as the other monotherapies and our combinations in a single study. And in that study, we don't plan to dose range in the maintenance setting. We plan to do quarterly dosing in that initial study. But with the half-life that we've observed, and we've also developed a high concentration sub-Q form of this, we believe that we should be able to hit the same trough levels and AUC levels that are achieved with Vedolizumab with a single shot every other month, sorry, a single shot twice a year. Twice a year. For the IVs, there was this IV cohort that you had, I think you presented a little bit of data. What sort of half-life we should expect for an IV, or is it too early to tell? So the precedent is that there is not a meaningful difference in half-lives between IV-administered drugs or subcutaneous drugs. Once they're in the plasma, they tend to have the similar half-life. So that's true for wild-type and YTE antibodies that once they're in the plasma, we see a similar clearance rate regardless of how the drugs are dosed. Got it. Now in terms of using Alpha-4 Beta-7 as a backbone, is there precedent or empirical data showing that this is a good backbone? I know you highlighted TNF and 23. What about Alpha-4 Beta-7? That's right. So the only randomized combination study that we have today is TNF and IL-23. However, there is substantial evidence for all three of the combinations that we're proposing. So for the alpha-4 beta-7 and IL-23 data, both we and others have shown activity there. The TL1A and IL-23, we've also seen published and internal data there, and we've been running studies across all three of ours in various animal and cell-based models of disease. So I think we have reason to believe that all three of these combinations make good sense from a whole different set of data. I think the idea that is quite compelling to me. We also saw an explorer study which was testing TNF and alpha-4 beta-7 together that showed additive benefit as well. We also know that, and we know the Vega study was TNF and IL-23 in UC patients. Alpha-4 beta-7 beat TNF head-to-head in UC patients within the Varsity study. We think it's a rational choice to replace the TNF in that combination with an alpha-4 beta-7 that is superior from an efficacy and safety perspective in that population. Got it. Now you are starting this basket study, right, or this big protocol that you're running. So do we need to wait for data from other programs before you start that study, or at least the Alpha-4 Beta-7 part can start? The latter, which is that the study is designed such that the arms of the study can start and end at different time points. The intervention-specific amendment related to Spy1, so describing the cohort that includes just our alpha-4 beta-7 molecule, we now have the data from our Phase I study to take and propose a dose for the Phase II study. We'll take that to introduce that cohort and start the platform study with alpha-4 beta-7 and placebo. Then when we have data from our TL1A, which we expect in the first half next year, we'll do the same. Then IL-23, second half of next year, we'll do the same. Got it. One final question on Alpha-4 Beta-7. Anything particular about the target, the way it is presented that you're able to get such a longer half-life, and how would that sort of translate to TL1A? I understand IL-23 is different, but just TL1A. Yeah, so going into this study, we had both the shortest half-life in non-human primates at 22 days for our alpha-4 beta-7, compared to 24 days for our TL1A and 30 days for our IL-23. So with no human data in hand, our expectation would have been that the alpha-4 beta-7 would have the shortest human half-life and would likely limit our dosing in our combinations going forward. We were surprised by the readout in Phase I for the alpha-4 beta-7, a much longer half-life than we had anticipated based on the non-human primate data. I could speculate, but we don't have a great explanation for why it was so much longer than we thought. I think it is incredibly helpful for us to be able to say with high probability that we'll have quarterly combinations now, because the TL1A again had a longer half-life. It's also a target that is sometimes soluble, sometimes cell-bound, which tends to lead to longer half-lives than fully membrane-bound targets like Alpha-4 Beta-7. And we have two of the TL1As as well that are progressing in parallel. So we really just need one of them to come out with a half-life in the kind of 45- to 60-day range to get us to be able to dose quarterly drugs. I see. So maybe just quickly on TL1A, how far behind is that molecule? And then I know you chose two. Maybe if you can characterize, are there any subtle differences between these two molecules? Yeah, that's right. So the TL1As, we have regulatory clearance for both molecules to start Phase I, so both of them will be dosing imminently. And so we plan to report the first in-human data from those molecules in the first half of next year as well. In terms of the two molecules, we picked two because we know TL1A can be an immunogenic target, and it is something that preclinical characterization of antibodies is not always perfect at de-risking immunogenicity. And so we decided to take two forward that we frankly think both have potentially best-in-class properties. They both bind to distinct epitopes between the two antibodies, but both are located on a single one of the TL1A monomers. They both have potency that is as good or better than any of the agents ahead of us in development. They both have a 24-day half-life in non-human primates, which again is more than double what we see for the TL1As ahead of us. And we formulated both of them at 200 mg/ml, which is also at the very high end of what's possible for standard subcutaneous formulations. So we think both of these look like incredibly promising molecules. We will test them together in parallel and then pick which one we intend to move forward after the Phase I study. Got it. I think you have said always that if you have consistent half-life, it's easier to combine, right? So do you or would you want to shoot for the exactly same half-life or somewhere in that 90-day range? But it seems like you're saying you need 45. That's right. So we don't think we need a 90-day half-life. We frankly didn't think we needed a 90-day half-life for the alpha-4 to be able to dose on this interval. We also developed very high concentrations of our alpha-4 beta-7 so that we may not actually have to use the full two mL of an autoinjector to be able to dose on a quarterly basis. And as we intend to move forward with co-formulations after this proof of concept study, having a meaningfully extended half-life on any of our molecules actually makes it easier for us to move forward with co-formulations that are dosed on an extended half-life basis because you may not need the full volume of any agent if you have a much extended half-life. The long half-life on Alpha-4 Beta-7 actually reduces the risk on the other ones because we may have more space in the injectors for those. That said, so we're still in the Phase II study. We plan to administer separate shots of these two agents. We think we need a 45-day half-life to dose quarterly and about a 60-day half-life to dose it on a twice-annual basis. Got it. What is your view on TL1A data? I think there have been some recent new long-term maintenance data that we are now seeing where the remission rate are reaching about 50%. Just curious to get your thought on the target in general. Yeah, I guess two things. So first, I think TL1A obviously is one of the most exciting new targets in this space. However, I don't think those data, or even really the induction data, suggest that it is kind of beyond the therapeutic ceiling of monotherapies on its own. So we love TL1A. We obviously think it's a great, exciting target in this space. I don't think it's going to deliver Vega-like efficacy on its own. And I think that's borne out in both the induction and the maintenance data now. Got it. The second thing, sorry, one more thing from the maintenance data that I think jumped out that was new as well is that we hadn't seen in the induction setting an exposure or dose response yet. Prometheus only tested a single dose, and Roivant had not reported kind of dose-dependent efficacy in induction versus maintenance until quite recently. These data now at UEGW just a few weeks ago suggested that for both of these agents, for both the Merck agent as well as the Roche agent, that the highest dose tested in the maintenance setting was the most efficacious by at least a few of the measures in the study. And when you do a dose response and see that the highest dose tested was the most efficacious, there's always a possibility that a greater target coverage result could lead to greater efficacy as well. And as we've talked about, our molecules have in the range of tenfold the potency of the Merck molecule, and we'd expect more than double, even more than triple the half-life of those molecules. We think it's something that we could readily test, greater exposure in the maintenance setting as well, and see if there is greater efficacy to be captured with that target too. Interesting. Interesting. Any view on the competing TL1A? I think there are a bunch of other companies working on a TL1A, and they have generated some interesting data relative to what Prometheus compound or Roche compound looks. Yeah, so I think, I mean, I think Prometheus, Pfizer, Roivant were really leading the way here on TL1A, and I think demonstrated this is an incredibly exciting target, not just in IBD either. I mean, I know we only have Phase II data in IBD to date that's positive, but there's a dozen plus indications where TL1A is implicated either with genetic, animal, or clinical tissue samples suggesting that it could be a good target in some very large indications. When we started working on the TL1A, we didn't take the approach that we did with Alpha-4 beta-7 and IL-23 in kind of having a molecule similar to those, but with an extended half-life. Rather, we thought that our molecules could be meaningfully differentiated than those first two across a range of different properties that I highlighted earlier. I think that gives us an opportunity not just to bring what we think is meaningfully differentiated into IBD, but also to explore these other indications as well. Got it. Then moving to SPY003, IL-23, what is the goal there? Because there, I think you can have even a much longer half-life. So how should we think about that? Yeah, I think, again, going into the Phase I data from alpha-4 beta-7, I would have said that the IL-23 was most likely to be dosed on at least a quarterly basis. The wild-type versions of p19 IL-23 targeting agents can be dosed on a Q8-week basis already in IBD. So we think the extended half-life version, we saw more than a tripling of half-life compared to risankizumab or Skyrizi in our non-human primate studies, and it's dosed Q8 weeks already. We think that that molecule has a very high probability of being dosed quarterly or twice annually given what we observed in non-human primates. We doubt that will be the molecule that limits our dosing in Phase II and beyond. Got it. You have also generated preclinical combo data that was just presented at UEG. Can you highlight some of the findings? What you are seeing, is there a particular combination that is standing out? Yeah, so I think the short answer is we think all of these combinations have a substantial amount of validity. I often start with human genetics where we see that variance in all three of these pathways contribute to the pathogenesis of IBD. We have animal models suggesting all three of these combinations have potentially additive efficacy, and then some cell-based models as well exploring kind of two of these agents together, seeing synergistic effects. When we think about kind of which of these combos we are most excited by, and we pose that to many of our SAB members and KOLs, I think many will err towards the alpha-4 beta-7 and IL-23 initially given the safety of those two targets. But certainly no one's ignoring the possibility that TL1A, which probably has the greatest monotherapy efficacy, could be the wild card that really drives the best results overall. Got it. Okay, what would be the timeline for these, like for readout, for the combination data from you, and also if you can comment on the Duet study, because I think that will be very transformative for the space as well that probably going to readout next year? Yeah, so the Duet studies we believe should readout next year, that both the UC and Crohn's disease studies have a one-year primary endpoint, and we know they're done enrolling. So we expect those readouts next year showing the TNF IL-23 combo across both Crohn's and UC patients in refractory patients now. So as compared to Vega, which was all naive patients in the refractory population, we would certainly expect lower overall response rate, but still I think we have keen interest to see whether the combination can outperform the monos in that context as well. I think if that's shown, I do think that will further demonstrate to the field that this is likely the way to go for not just naive patients, but also patients who are refractory to prior biologics. So I think in that same timeframe is when we anticipate kicking off our study. That platform study exploring what we hope will be quarterly combos of our three agents, we expect to kick off mid-next year. It is approximately the same size as the Duet studies, which are enrolled in a little over 18 months and that had a three-month primary endpoint. We will provide more clarity on exactly when ours will readout, but that is a reasonable indication of how. But your study, the platform study is not limited to naive, sorry, exposed patients, right? That's right. Our study, we plan to include both naive and refractory patients. What do you think is the bar there? How much delta do we need for this combination to sort of get the frontline share? Yeah, I mean, I think we saw what was observed in Vega, which was almost a directly one plus one equals two effect. When we speak to physicians, I think one plus one is two is obviously great, but if you ignore it for the fact that they're combinations and you saw one plus one is 1.5, and if you don't see a safety effect as well, it's hard to argue why you wouldn't use one plus five versus one if you had no difference in safety. I also think in the long run, products that are co-formulated as a single shot, which J&J has in the Duet studies and we will have in our program as well, I think frankly they should be priced like a single agent as well, not like combining two branded drugs together Therefore, I think if you have greater efficacy, similar safety, and similar pricing, I don't see why that wouldn't get used in a substantial portion of patients. I mean, if you look at the new drugs that are approvable, 12% delta is enough. So I think that should also hold true for combination. If you can just improve 12% versus mono, that should be the bar? Yeah, I think. You need to double it. I don't think you need to double it. I think the Vega results set an excellent place to start. I don't think we're going to see a kind of, certainly not going to see 50% remission rates in a refractory patient population, but I don't think you will need to for this to actually be clear that this is likely the future of the field. Very good. How is the financial health of the company? Yeah, so we fortunately did three financings over the last 18 months, raised about $570 million between those financings. We still have over $400 million on the balance sheet today. It takes us well into 2027 on that runway, which we think allows us to readout plenty of catalysts over that time and then hopefully demonstrate continued value. Very good. Cameron, that's all I had for you. Thanks for your time.