Good morning, everyone. Day three of ourJefferies London Good morning, everyone. Day three of ourJefferies London Healthcare Conference. My name's Akash Tewari. I'm a pharma and biotech analyst. Here at Jefferies, I have the pleasure of hosting the Spyre Management team. Cam, why don't I hand it off to you for some intro remarks? Sure. Just as a brief background, Spyre is a phase II biotechnology company advancing a series of products in autoimmune diseases, including inflammatory bowel disease and rheumatic diseases. In each of these spaces, we're taking what we think are optimized or improved antibodies against what we think are de-risked targets. In inflammatory bowel disease, we're developing them both as monotherapies, where we think we can meaningfully improve the convenience of products and hopefully incrementally improve efficacy as well. Also as combination products, which we think could represent a step change in the care of inflammatory bowel disease treatment. In rheumatic disease, rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis, we're advancing what we believe is a best-in-class TL1A antibody. There, we actually think we have a first-in-class opportunity with a product that is ahead of the ones that were actually developed before us. Okay. Very helpful. Cam, it's obviously good to see optimism kind of return in the space. And really I think people are recognizing the strategic value of assets. I think I want you to talk a bit about the delta between perception and then actual strategic value. A good analogy I want to give is on Metsera. I think if you were to look at that company on paper, you would say, "Okay, I have known targets that are long-acting, and other people might be ahead." Yet there is obviously strategic value there. Can you talk about the clinical development plan to actually make co-formulations, what you have to do, and then when you can actually have co-formulations that play nicely with each other and you can really modulate the ratios of how much you're hitting targets, what is the strategic value of that, both for you and then maybe more broadly? Yeah. Maybe just briefly, why do you have to do this in IBD? I think it's just worthwhile to mention, which is that the monotherapies in IBD, we just don't get to the level of efficacy that you would hope for. Really a devastating disease, really expensive consequences both to patients and to the healthcare systems, right, in terms of the downstream hospitalizations, surgeries that these patients go through when they have flares of this disease. We have a half dozen approved mechanisms in IBD. You don't get above about a 25% level of clinical remission. It's a disease that's multifactorial in terms of what drives it. The idea that there's a single bullet in terms of that's going to lead to complete remission in all patients, that seemed unlikely at the get-go. I think we've seen that as we've developed a range of classes that you just don't get there. The idea of combination therapy in hard-to-treat I&I diseases makes a lot of sense. I think we have really a lot of evidence now from real-world studies, animal studies, human genetics, and a handful of randomized trials in the space as well that suggest that you can get meaningfully incremental efficacy when you add multiple mechanisms together. Now, to do that, as you kind of highlighted, is not trivial. To get to combination products that adequately hit both targets and blockade them to the level that you would expect, we've always thought the best approach to do this is to co-formulate antibodies because that retains the high specificity, selectivity, and the antibody properties of each of the individual components and lets you get that complete blockade of both pathways simultaneously. It's hard to do, though. You can't just mix any two antibodies together and form a co-formulation. They can be unstable. They can form precipitates. You can lose them in solution. You also have to run combination tox studies as well, which we've done for each of our combinations as well and shown that not only our individual products have no adverse effects, but so do our combinations. We have no adverse effects at any level for any of our combination products. We have co-formulations of our antibodies that are 200 mg per ml, which is the very high end of what is achievable for any individual molecule. We can do that over a pretty wide range of ratios that lets us really optimize how much of this target we need versus how much of that target. It is a lot of work to get to the point where we are, which is moving this into a big phase II study to see whether we can get those optimal combination products. Makes sense. I think the other thing that's kind of interesting, I started the panel, our healthcare conference on Monday with the panel, and I was hosting John, who was the founding CEO of Alnylam. His new company, they're actually he's going for primary prevention with long-acting known targets. It's funny, in a post-biosimilar HUMIRA world, I think you maybe don't think of biologics moving into first-line therapy. I think IBD is kind of a unique one because you have to get surgery, and it's incredibly costly in a way that maybe it's not for atopic dermatitis, skin conditions. I'm not sure we should really dismiss the first-line opportunity out of the gate. Can you talk about, from a payer perspective, if you had a therapy where you can get to quarterly dosing and a meaningfully higher amount of efficacy, what that actually means in terms of downstream costs? I know your team has looked at this. Yeah. I think if you zoom out over the last couple of decades in IBD care, the broad theme is what they call top-down therapy. There are dozens of studies across a range of different markets. These are health economics studies where you're basically testing whether bottoms up, meaning start from conventional therapies and work your way up to the best things out there, or top-down, meaning start with the best things and then try the other things later, is better. And the short answer is that it's much better to start with the best option that you have and then try other things once you lose remission because many of the consequences of IBD are extremely expensive and can be irreversible in terms of the damage of the disease. To both the patient and the healthcare system, it's the right choice to use the most effective thing first. I actually think we kind of already know the answer, right? There's only one great randomized study in IBD that's been done testing monotherapies versus combination therapies, and it was done in the first-line setting. It was done in naive patients that hadn't been exposed to prior biologics before. We saw almost a 25-point delta on clinical remission, kind of better than what you get for most monotherapies over placebo in this space, comparing a combination to the monotherapy components. I just think that delta is worth reflecting on because we're looking at the scale of products in IBD today. We see both the guidance for both TREMFYA and SKYRIZI in IBD, sort of mega blockbuster guidance, right? High, mid to high single-digit billions of sales. They beat a biosimilar by about 10 points, right? They beat either HUMIRA or STELARA by 10 points. These products are expected to do mid- to high single-digit billions. If you have a product that beats those drugs by 10, 15, 20 points, and we've seen 20-plus in the naive setting, I think these products could be very large in this space. It is going to make sense certainly to patients and physicians. I also think it is going to make sense to payers and healthcare systems to try and get and keep patients in remission here. No, I think that's right. I think part of that also then becomes like, does your team have the aperture to explore that yourself? And then also, do you feel like you're capitalized to really think about that? I know we'll talk about the DUET data, the AFFINITY data, some of your initial data that's coming up. As you start thinking about phase III development and the flexibility you have, would your team be interested in kind of exploring, A, not only getting data post-HUMIRA in a TNF refractory setting, but actually exploring that first-line opportunity and getting that on the label? Yeah. I think, I mean, one of the maybe this is the nice precedent of IBD is that most products that are approved in IBD run pivotal trials that are in a mixed population. In mixed, I mean here a roughly 50-50 mix of naive patients, so that first-line population combined with a refractory population, people that have failed other products. I think, and we're actually doing a similar design in our current phase II study, but we will see this answer in the next year, year and a bit in terms of seeing kind of both our monotherapies and our combinations in this broad swath and start to develop the data set that would justify use in both populations. Understood. Now, I think we're probably going to get the DUET data at ECHO. That's what we hear. We'll see. It may never come out. I think we've also started to, with some of the combination data sets that have come out, not just in IBD, but more broadly, look at the AFFINITY trial, you're seeing where there are limits and then where there are instances where 1 + 1 really does equal 2 in combination therapy. Heading into the DUET study, where do you feel like there is going to be a benefit shown? What endpoints would you point investors to to really suss that out? Once we have that data in hand, think about what's the read across really to your drugs because each individual component, how does that compare to what Spyre has internally? Yeah. I think what's interesting about the J&J development program is I think we and most of the field look at it as both validation for the combination approach and, on the other hand, competition as I think one of the better combinations in development in terms of data to date. On the validation front, frankly, I think we have enough to justify this approach with what we have already. I mean, we have tons of evidence from real-world studies. We have animal studies. We have human genetics. We have all sorts of evidence that kind of this is likely the future of IBD care. I think we feel very strong about that point. From a competition perspective, I think the J&J is really, they're setting the bar here as kind of the first combination therapy in this space. I would frankly be a bit surprised if in the long run, that combination, particularly using golimumab as a component of that combination, will be the long-run best combo. That rationale is really of the half dozen approved classes in IBD, TNF, I do not think anyone would argue is one of the top three in terms of the casita safety risk ratio. Even within the TNF class, I would not argue that SIMPONI is even in the top group of TNF inhibitors either. The idea that that combination is going to be the winning combo in the long run, I think is pretty unlikely. To get to kind of how DUET matters or not to us, I think what we are likely to see, I mean, this is taking that TNF combo with SIMPONI into a population that has all failed another drug. It's a fully refractory population. Most of those patients will have failed a TNF. Most of them will likely have failed, frankly, a more efficacious TNF, infliximab or adalimumab or one of the other TNFs that probably is more active than golimumab. I really doubt that we're going to see a VEGA-like response, right? I highly doubt you're going to see that level of efficacy when you're taking one component that I think is inferior to something that they've probably failed already. That said, the AFFINITY trial, which you alluded to, gives us some suggestion that even in a TNF- refractory population, you still do see benefit of the combination. They nearly doubled the ACR 50 on the combo compared to the IL-23 alone. Again, this is TREMFYA, right? This is the mega blockbuster product that they're showing these substantial deltas above. In that population, I think that was shockingly good to us, frankly, to take a fully TNF refractory population and show that incremental benefit. Yeah, hopefully we'll see the DUET data soon. I think it will help inform kind of where you see efficacy improvements of the combo versus the monotherapies. I frankly think there's plenty of validation for what we're doing. I think we're highly likely to see additive efficacy between our combinations. I really also think that the design of our combos is likely superior to that J&J combo as well. I'm not sure there's many major changes that we would make regardless of the outcome of that study. Understood. Can you talk a bit about, you have talked about the combo, if we can show kind of a 10% bar, that would be clinically meaningful. I do not think you just came up with that number. There is feedback that you have gotten from doctors and I think more broadly in the space that helped lead you to set that bar. That is also, spitting out that number comes with a complicated equation because you have to go with exactly, as you mentioned, refractory patients and then naive patients. You think about the milieu that you are actually taking into a clinical study. So can you talk to us about, in both that kind of naive and then in that refractory population, what you are aiming to show in order to get that 10% bar that you have publicly stated? Yes. I mean, where does that bar come from first? I think it's, you mentioned we've done plenty of market research among gastroenterologists, among payers as well. Kind of right around that double-digit delta is where you see, look, this is a clinically meaningful difference between products. Now, I take all market research with some grain of salt. Actually, I rely more on the precedents in the space, which I think actually line up pretty darn closely with that as well. We have three good head-to-head trials in this space that have led to meaningful practice shifts. The first was the VARSITY study of ENTYVIO beating HUMIRA, just under a 10-point delta led to ENTYVIO being a mega blockbuster product in this space. We have had two actually similar deltas with the P19 IL-23 inhibitors beating STELARA, either just under 10 or just over 10-point clinical remission deltas, and again, leading to those products being mega blockbusters in this space. I think that 10-point range is both what we see in market research and what we see in previous studies in terms of what it has taken to meaningfully shift practice. In terms of how you get to 10 points, look, we have seen what a first-line combination can do, like north of 20 in terms of that population. We have not seen a fully refractory trial yet. I doubt you are going to see a 20-point delta in a refractory population. I think you need to get to that roughly 10 in a 50/50 mix. As long as you see that level of efficacy delta without a safety decrement, and you can price it like one drug, as in you can dose it together, coming back to our co-formulation argument, you can dose it as one thing, you can price it as one thing, I think that's likely to be a dominant product in this space. I think we frankly have three high-probability shots at that, right? I mean, these mechanisms that we're testing are orthogonal mechanisms. They block different paths of the pathophysiology of the disease here. They're three of the safest mechanisms in IBD. We can dose them together on, frankly, our combinations I expect to be more convenient than most of the monotherapies that are on the market today. I think we have three high-probability shots at delivering that type of product. Can you kind of go over the three combinations that you are pursuing? Why go with three different approaches, right? Because it is capital-intensive to do that. What optionality does it give you? What are the biological questions that each one of these are kind of asking? So, the three mechanisms that we're pursuing first is Alpha-4 beta-7. This is an anti-integrin approach. It's blocking the trafficking of immune cells into the gut. Then two cytokine approaches. One is targeting TL1A and one targeting IL-23. These, I think in general, are three orthogonal mechanisms. They all have downstream pathways that do not completely overlap, I think are likely to engage different parts of the biology that's driving IBD. I think there's quite likely that you're going to be able to see incremental efficacy of any of these two things together. We've actually seen that both in, we've looked at some human genetics that would support that idea. We've also tested these together in animal models of colitis and seen that at any given dose of two molecules, you see more when there's two on board than you do with one. I think this all supports the idea that you're likely to see incremental efficacy here. We also didn't just pick this from biology and efficacy. The safety here, I think, is paramount because if you see a drop in safety when you move to combination therapies, that's going to be tougher to come first. You may get used more like a JAK where you have to get used after a few things. Alpha-4 beta-7, I think it's fair to say, is the safest approved class in IBD. It's a gut selective mechanism as well, which means you don't get the broad immunosuppression effects that you might see with other classes. I think you are quite unlikely to see additive immunosuppressive risks. Whereas, and then IL-23, I think it's fair, is the second safest class in the space as well. You never know how combinations are likely to work, but safe plus safe is probably the best bet. Again, we've replicated that in animal studies as well where we haven't seen any either individual toxicity or combined toxicity with these programs. Sure. Now, I want to talk a bit about the maintenance setting and we think about TL1A. Obviously, Teva and Sanofi are moving forward. Look, that's a very potent drug from our diligence. It does have limitations in half-life. I think there is a risk, of course, you're going to take with a really potent approach. They're kind of, let's say, nuking the targets out of the gate, and then they're seeing what they can get away with in terms of maintenance. I think there is a shot that they are actually able to come up with a viable maintenance therapy where there's really not a non-inferior decline in terms of efficacy as they do spread out the dosing to, let's say, monthly or more. You know what's kind of interesting, and I don't know if this is unique to IBD, but it's an interesting case study of it, is with the amount of exposure you're getting for the target and you're spreading out the dose, is there a shot that you can actually see efficacy improve in a maintenance setting? I don't think that's been the bar historically. I'm not sure you've talked about that a ton either. When you guys think about what you want to show and what's the diligence as you get longer duration, is it possible to actually see efficacy continue to rise? Yes. Maybe kind of first principles for us, the advantage of an extended half-life, and we talk quite a bit about convenience. Actually, I think that will translate to adherence and likely in the real-world setting, potentially seeing better efficacy with our products overall. Kind of a, I would say, underappreciated aspect of long-half-life drugs is that you can narrow the peak-to-trough ratio of them, meaning you do not do what you just described in terms of nuking the target at the beginning and then hoping you can cover it at C-trough. It is the opposite here, right? We actually can give substantially less drug to get the same trough levels. I mean, half-life is an exponential decay. The fact that we are seeing triple the half-life of our molecules relative to others means we can get meaningfully higher C-trough levels even with lower Cmax levels of these drugs. It's a really substantial advantage that lets you fully cover these targets without risking some off or on-target effect by having way too much drug on board at the beginning. Now, in terms of maintenance data, can you see an improvement relative to the first-generation products because of this? I think it's possible, especially with TL1A. I think you see that kind of in some of the phase II programs when they move to phase III, they actually increase the dosing frequency. Merck specifically went from Q4 week dosing in the phase II study, and they doubled the dosing frequency down to dosing every other week. That drug has a much longer half-life than the Teva one does, and they're aiming to dose monthly. I think with the half-life that we have and kind of these high-concentration formulations that we've developed, we have an ability to both extend the dosing frequency and still improve the C-trough levels of the drug. I think it gives us a shot at improving efficacy and convenience without driving any safety downsides. Are there, let's say, endpoints that we should be looking at in terms of, again, you've kind of controlled the underlying disease, and now it's really about the body healing over time? Are we thinking about the really stringent remission-like endpoints? Are we thinking about maybe some of the less stringent primary endpoints that we see in IBD? Where do you feel like that benefit might start to manifest? I mean, the endpoints in IBD tend to be threshold-type measures where you basically, you're measuring a continuous variable, but you're then setting a bar of this is response, this is remission, this is steroid-free remission, this is yet again higher. I expect what we'll see is that the bar that we want to differentiate on with more and more effective products, particularly combinations, that bar I expect will move up, meaning getting a response shouldn't be good enough anymore. That's really not what physicians are targeting for their patients. It's certainly not what patients to just respond to a drug. They want to be in remission. I mean, the ideal situation here is people forgetting they have these diseases, right? That is the best-case scenario. That is what we're ultimately aiming for is long-term remissions where you're forgetting that you have this serious disease, where you don't have a shot in your fridge all the time because you have to take it every week or every other week. You don't have to take a pill every day. I think people kind of forget that IBD, the median age of diagnosis, is around college years, which means half are younger. You are talking about kind of kids, college-age kids, young adults who are having to take medications all the time and then not getting into long-term remission. I think what we're aiming for is something that would be a meaningfully different standard of care for these patients. Understood. Now, you're going with this kind of novel design where I think you're doing a lot of the work in terms of contribution of components early. That also leads to larger kind of phase II studies as well. Can you talk about, again, we go into this no overlapping toxicity question, which is, again, I think almost purposely nebulous with the FDA. Can you talk about maybe interactions you might have had with the agency and how they've really looked at your design here? Once we get through these phase II readouts going into next year, how much do you feel like you've really answered the" contribution of components" question? Yeah. I think we've been pretty direct in our interactions in terms of what we're trying to do really from early days here in terms of design, even getting input on things like our combination talk studies to make sure that we're designing them to enable the type of study that we want to run. Of course, discussing the design of this phase II trial as well. I mean, it's a master protocol design, meaning it actually comes with its own IND for the design of the phase II study overall. I think we're very direct in terms of our goal here is to test contribution of components that we want to see. You can see that in the design of our trial, a placebo, the monotherapy components, and then the combination in the same trial setting. I think we and most of the other sponsors who I think are serious about developing combinations in this space, I think J&J obviously with the design of their studies, I actually think ours is kind of similarly robust in that design. I think some others are taking a few shortcuts in terms of not having a placebo, having open- label designs. I think it's a relatively robust approach at aiming for contribution of components. Of course, you get no credit until you show the data, but I think the design here aims to achieve that. Understood. Now, maybe just stepping back, I think to your team's credit, you started to really explore the external biology of where TL1A can go. I think you've seen actually some of the pharmas catch up with what you're doing. It is also interesting, I think Merck was also in one of those panels, and Prometheus was really originally a biomarker company, right? I think in its heart, that was the approach that made the most sense. That is really, I think even if you talk to clinicians, there's a subset of them who are really interested in exploring more rational biomarker-driven treatment. Maybe that doesn't make sense, I think, in these larger IBD indications because A, you can go with combo, and B, I think you're seeing this become a bona fide target. As you think about maybe you have multiple TL1As and there's different price points you can go with these diseases, should we think about a biomarker-driven strategy and patient selection with some of those orthogonal diseases? Also, could you think about combination approaches there as well? Yeah. I think both combinations and patient selection strategies are aiming for a similar goal, which is how do we improve that efficacy, right? That 25% clinical remission, clearly not the best, or clearly hopefully not the best we can do in these spaces. It is a very heterogeneous disease with multiple pathways. I think multiple pathways that in any individual patient and different pathways in different patients. I think what that lends you to believe is basically that you could either identify patients whose disease is driven by one particular thing and have a biomarker or companion diagnostic to identify those patients, or you block multiple pathways and you can hopefully achieve that in more than a broader swath of the population. I have a genetics background. It's actually, I would love to see that be the right answer here in terms of identifying people that you can reliably select to respond to a particular mechanism. I think the data to date would suggest that the power of blocking more than one pathway at a time is likely greater than that. I still hold out hope that we will identify subpopulations that look more like a monogenic Mendelian disease population and you get kind of 75% remission in a subset of the population. I do not think we have found that yet. I think our trial actually will be one of the most interesting places to look for it because we are testing both three mechanisms individually and three combinations together. I think we will have a really powerful ability to kind of look at the broad IBD population, both naive and refractory patients, see who responded to what. I think you could end up with a more compelling case of what to find. Now, outside IBD, I think some of the diseases that we're looking in rheumatic disease, I actually think they kind of look like IBD in that you don't get complete responses and remissions to any individual mechanism as well. I think it's quite likely that we see that combinations is not just an IBD phenomenon, but it's a hard-to-treat I&I disease phenomenon. I expect that will likely expand as we see individual mechanisms work. Understood. We're out of time, but I really do appreciate it, especially early in the morning. Thanks so much for everyone for joining us. Thanks for having me. I really appreciate it.