Good morning, everyone. My name is Yatin Suneja, one of the biotech analysts here at Guggenheim. Welcome to our healthcare innovation conference. Our next presenting company is Spyre. From the company, we have a few executives here in the room, but I will be chatting with the Chief Executive Officer, Cameron Turtle. Cameron, next year is going to be pretty busy for you guys. Why don't you just maybe set the stage, talk about the key things that we need to focus on, and then I'll go into some of the assets that you have. Yeah, of course. I think our strategy is really three pieces that are contained in two large phase II trials. First, in inflammatory bowel disease, we're running a study called the SKYLINE study, and that is using three assets. These are all what we think are optimized, better versions of what we think are the three best biologic targets in IBD: alpha-4 beta-7, TL1A, and IL-23. We have long-acting versions of each of these antibodies that we think can dose on a quarterly or twice-annual basis, and we think are likely to match or potentially even exceed the efficacy of the first-generation molecules. I frankly think in today's IBD market, they would be leading products in the IBD market today as those monotherapies. However, I think it's quite likely that the future IBD market doesn't look exactly like today's market in that we, and I think almost every serious strategic in the space, is exploring combination therapies in IBD as a way to potentially meaningfully improve the efficacy that we see with monotherapies, and hopefully don't see any safety downsides. What we're testing in the SKYLINE study is all the pairwise combinations of those antibodies. Alpha-4 and TL1A together, alpha-4 and IL-23, and then TL1A and IL-23 together. We think our combinations are really uniquely differentiated in the inflammatory bowel disease development pipeline because they're all long-acting antibodies against these targets. Our combos will be long-acting, and we think could be really differentiated products. Outside of IBD, we're running a separate trial called the SKYWAY study, and this is exploring what we think is a potentially best-in-class anti-TL1A molecule, again, dosing subcutaneously quarterly or twice annually in a basket of three rheumatic diseases: rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis. In those areas, we think this product profile with safety for TL1A currently looks quite good. The dosing profile, as I mentioned, if we can see efficacy that matches the other classes, we also think this product could be a leading market or a leading product in those markets as well. That is our strategy kind of within IBD and then in rheumatic diseases. We really think the catalyst map from those two trials is pretty unique within biotech as well. Between those two studies, we're expecting six readouts next year: three in IBD, three in rheumatic diseases, and then to follow with the combinations in IBD. Got it. Very good. Maybe we'll pick the IBD piece first. You have three assets: alpha-4 beta-7, TL1A, and IL-23. Can you just quickly remind us where exactly you are on the dosing frequency for each of these molecules relative to what is approved right now? Sure. For each of these molecules, we've now reported phase I data, actually just recently, last week for the last data set for our IL-23 antibody. We've seen for all three of these antibodies that they have meaningfully extended half-lives, approximately 3x or more compared to first-generation molecules. What that's going to allow us to do is in the SKYLINE study, we'll be testing both a quarterly and a twice-annual dosing frequency for these monotherapy doses. This is meaningfully improved compared to what exists for each of these targets. On alpha-4 beta-7, Entyvio is dosed every two weeks. The TL1As are dosed every two weeks or every four weeks in the phase III studies. The IL-23 is a Q8. In all cases, a meaningful improvement in convenience compared to first-generation molecules, and then also sets this up for kind of, frankly, combinations that have improved convenience compared to the monotherapies on the market today. Got it. So you own all these three assets. Is there a benefit of having consistent half-life across these three drugs or across this portfolio? Because eventually the goal is for co-formulation, which I think is not the case for, let's say, pharma, because a lot of these half-lives are inconsistent. Can you just talk about that dynamic a little bit? Yeah. I think the advantage of developing a portfolio for combinations from the outset is probably an underappreciated challenge. What we have with antibodies with similar half-lives across all three, and we've developed co-formulations that are 200 mg per ml for each of these co-formulations as well, meaning we can get a lot of antibody into a single shot, even mixing these antibodies together. This is something that folks that are trying to get into combination therapies but didn't design them from scratch have a very difficult time doing, which you can see in some of the trials that have been launched. For example, we see large strategic companies that are mixing dosing intervals between their products are unable to blind between the arms. Mixing a Q2 week drug with a Q4 or Q8 week drug, as you can imagine, those combos then require a lot of different injections. I think we even have seen examples quite recently of strategics that are combining kind of orals with injectables, which I think, A, is very difficult to imagine how that becomes one product in the long run. I think from a pricing and access perspective, it is also quite tricky when you're talking about an oral medication combined with a biologic as well. I think our approach is differentiated. It is hard to replicate and is something that I think we're meaningfully ahead of even some of the largest players in the space. Got it. Let's discuss the SKYLINE- UC study, and then I'll come back to the J&J DUET program. For the SKYLINE- UC study, you have its part A and part B. In part A, you are testing monotherapies, right? Then you go into combination and do some dose ranging work there. What exactly would you want to show in part A, because that's the data that's going to come next year? Like, how will we know that you have these active drugs? What is the benchmark there? Sure. For each of our targets, as you mentioned in part A, we're running these open-label cohorts where we're going to see really preliminary safety and efficacy of each of these products. We're using, because it's an open-label context, kind of objective measures of either histologic improvement and endoscopic improvement that I think will give a real indication of whether these drugs are having a benefit or not. Of course, we'll also be looking at normal measures like clinical remission, but in the context of an open-label setting, you would probably lean on the objective measures more. I think in IBD, we've seen kind of a variety of histologic improvements, endoscopic improvements for a range of different classes, including the ones that we're testing, and we can benchmark our efficacy in part A against those. I think in general, what we hope to see is that each of our agents is approximately as effective as the first-generation molecules. Ideally, we would see something where we see some improvement as well. I think it's really just a preliminary activity of these drugs that we'll see in a year later, the full readout with those in combinations. Will be able to, just in the monotherapy, will be able to figure out the dosing frequency for these? Like where are we going to land up? Yeah. The initial readout is just going to be the induction readout at week 12. We will not be looking, of course, we will read out later the maintenance data where we are testing on a longer duration. In the initial readout, it will just be the induction efficacy. Okay. How big are these individual arms for these studies? They're a little over 30 each. So these are kind of approximately 100 patients total for the three cohorts. I think in IBD, we've seen cohorts of that scale on de-risk mechanisms with kind of a more convenient approach. I actually think that is kind of a value-creating event. We've seen recent examples of data sets leading to acquisition of these companies. I think the oral alpha-4 beta-7 is the most obvious recent example. And I frankly think when we do market research and test a quarterly or twice-annual dosing profile of an anti-alpha-4 beta-7 biologic, it would be preferred to a once-daily, let alone a twice-daily oral. So I think these data sets probably have underappreciated value in terms of what these are worth. I think when strategics in this space are looking at their combination strategy, our assets, even though our assets are best together, they're also better for someone else. Why would you combine with an every two-week drug if something's available that's twice a year? I think the value of our assets should be de-risked as we get through these safety and efficacy readouts. How is the enrollment for these, the part A? Can you just also talk about the type of patient? Are they all naive you're targeting? Is it 50/50, 60/30, whatever the split is? Yeah. You can see the progress of the trials is posted on ct.gov. We list kind of the regions and sites that we're approved in. I think we were optimistic that we would see high enthusiasm because it's an open-label setting with a convenient version of mechanisms that are de-risked. I think that's what we're seeing to date. I think there is a lot of enthusiasm and excitement for this, kind of the certainty that you're getting a long-acting version of a biologic targeting something that you know has been seen. We'll provide an update on enrollment as we get there in terms of timelines. So far, the enthusiasm is what we would expect. Okay. And then part B, like when will that start? And why are you doing dose ranging in part B? Yes. Part B, it'll seamlessly transition to part B as soon as we're done enrolling in part A. As soon as we enroll that approximately 100 patients across the alpha-4, TL1A, and IL-23 part A arms, we'll immediately start enrolling in part B. In part B, we'll, as you mentioned, do two doses of the monotherapies and then the single high dose of the combination. To answer your earlier question, we are targeting approximately a 50/50 mix of naive and refractory patients in the study overall. Got it. I mean, the combo approach works. We saw that with VEGA. Can you maybe help our investor? I think there is some confusion regarding the DUET study. I think it's a unique patient population. I think people want to see that. In the real-life setting, when we talk to even physicians, they are using these types of combination approaches. What is the difference between the VEGA study and the DUET study? What is the relevance of this J&J DUET study? I was picking a theme at the UEG. It seems like the data might come only next year, and there was some excitement, but I couldn't figure out how much of an excitement there is. Yeah. Maybe just kind of to step back for the combination thesis overall, this did not come out of nowhere, right? I think in general, we have been working on mechanisms for IBD for a few decades now. We have about a half dozen approved classes. None of them break what the physicians call the therapeutic ceiling in this space that you get maybe a quarter of patients into clinical remission and then end up having to cycle through many, many different mechanisms. The idea that blocking more than one pathway could lead to better efficacy is relatively obvious in a disease that is not driven by a single pathway in any one patient and potentially a different set of mechanisms in a range of patients. Across, there is human genetic evidence that points to multiple pathways being involved. There are animal studies that demonstrate that blocking more than one pathway is effective. As you pointed out, there's been tons of real-world evidence looking at a range of different combinations showing that they can see, in most cases, some level of additive efficacy without incremental safety effects. I think that was meaningfully supported with the VEGA results, which you referenced. That was the first randomized controlled trial looking at TNF and IL-23 together from J&J. They showed that they roughly doubled the efficacy of the monotherapies in a naive population. J&J followed that up with three other studies, right? A psoriatic arthritis trial called Affinity in TNF refractory patients, and then the two DUET studies, again, in refractory populations overall. I think that is the main change from VEGA to those studies, moving from an all-naive population to an all-refractory. I think it's particularly challenging because it's a TNF combo in a TNF refractory population. In fact, I think it's fair to say that Simponi is probably not the preferred TNF alone. You're taking a failed mechanism into a group that has already been testing a combo where they already failed one of the components. I think it is a much more challenging population to see a big delta in. That said, I think we're still interested in seeing what that result looks like. We'll, of course, keenly look at it and see if it impacts our strategy. I think it's quite unlikely that we would change what we're doing based on that result. Got it. Got it. Like Affinity was in PSA, but I think they did see some benefit. It was a similar sort of a concept there also. Yeah. I think that trial was frankly set up for a pretty challenging way to see a combination benefit. Again, it was all TNF failed patients that either got IL-23 alone or got TNF plus IL-23. On some of the key endpoints in that trial, like ACR50, the combo still doubled what they saw on the IL-23 alone arm. That gives me somewhat more confidence that we'll see additive benefit in another refractory population. I think that's a much harder place to see a benefit. Yeah. So I think the J&J DUET study basically comes down to the type of patient. If they end up enrolling a lot of TNF refractory or exposed patients, the likelihood that they will further respond is obviously less than versus you get the alpha-4 beta-7. So it's not that clear. Yeah. I think in general, I think the probability that the Spyre combos, our combos, will outperform is quite high. I mean, alpha-4 beta-7 beats TNF head-to-head in this population, the Varsity study. TL1A would almost certainly beat TNF head-to-head too. That study hasn't been run yet, but the data and a cross-trial comparison looks very compelling. The idea that replacing a TNF in those combinations with either alpha-4 or TL1A would lead to a better result, I think is quite high. Also, not having a population that has all failed one of your mechanisms, I think is also quite likely to. Can you drill down a little bit more into this point? Because I do agree that you do have these three combinations. If somebody fails on one, you can put them on a different. Just talk about that dynamic that's set up. Our trial is a tree-through design. We won't be re-randomizing to different combinations during the study. I think we will see, as I mentioned, we'll be running a 50/50 naive refractory population. That refractory mix in our trial will include TNF failures, will include Stelara failures, and other mechanisms that are out there. I think it will be very interesting for us to look on the back of the SKYLINE result in terms of what type of patient was more likely to respond to each of our different combinations. For example, the Stelara failure patient doesn't need to go into Skyrizi arm, right? Can go to alpha-4 and TL1A, which other companies don't have. That's right. In our part B, it is a randomized study. I think we will get to see patients that have failed Stelara go on to a combination of alpha-4 beta-7 plus TL1A or TL1A and IL-23. We'll get to see all these different outcomes. Now, when we fast forward, when you have your own data in part B, like what is the goal? Like how much incremental efficacy you need to put in order for this combination to be appealing to physicians? Yeah. So I think in IBD, I think what's nice is we actually have quite a few precedents of what is sufficient to drive a meaningful market shift. To cut to the chase, I think it's about a 10 percentage point delta in clinical remission is a clinically meaningful difference that has led to massive market shifts. The first is Entyvio beating Humira in the Varsity study. More recently, we've seen the two p19 inhibitors, Skyrizi and Tremfya, beating Stelara by about that percentage delta as well. All of those drugs are either doing or expected to do high single-digit billions in sales in IBD. I think that is just worth remembering. That is a 10 percentage point delta over Stelara, which is now a biosimilar. I think if products like ours, a combination, shows that level of delta relative to the existing drugs, the branded Skyrizi, Tremfya, IL-23s, if you show a 10% delta over that, I think it is just a different level of product in this category and would be a dominant product in this space. Got it. Would you have any expectations for DUET? Like what would you like to see or what are you hearing? I mean, I can tell you, I think we hear about 10% is what people want to see. I think 10% would be an extraordinary outcome in an all-refractory population. When I talk about a 10 percentage point delta as meaningfully shifting clinical practice, that is usually in a phase III study that is a 50/50 mix of naive and refractory patients. If you see a 10-point delta in an all-refractory population when you've already failed one of the two components of the combo, that would be a very surprising result to me. Okay. Very good. I think I'm good on that. Maybe moving on to the rheumatology side. I mean, that's one piece of the story which I think people are still not paying enough attention to. I do believe that TL1A are not further, are not too behind on the TL1A side. Just talk us, like, what are you hearing from investor? What is your pitch on the rheumatology side? Yeah. I think in general, I mean, most of our molecules are kind of me-better biologics, right, in terms of a reason that we have an improved product and come into this space a few years later. That's actually not the case for our TL1A in rheumatic disease. I think there we have a molecule that we think has meaningful advantages relative to the other TL1As that are in development. We're not behind. We're actually ahead in development in these rheumatic diseases with a product that has meaningful properties above and beyond what the strategics in this space own. I think we and Merck and Roche agree that TL1A has a compelling case to work in these rheumatic diseases from an efficacy perspective. When we compare the product profile that we're developing, again, a quarterly or twice-annual dose product, most products in these spaces that we're talking about carry boxed warnings or substantial safety precautions that we currently don't see for TL1A. If we have meaningfully improved convenience, a cleaner safety profile, and then we see efficacy that's in the range of the existing products, I think this is a leading product in these rheumatic disease spaces where we are first and best, which is usually a good position. Got it. So you're running this basket study in RA, PSA, and ECSPA. Which one of these studies are going to read out first and what exactly we need to see? I think there are some uniqueness also, like the RA study has dose ranging. Just walk us through that. Yeah. The design of the study is a basket study with somewhat independent sub-studies. The advantage of a basket is that once you get a site country activated, you get to enroll across all three of these sub-studies. The sub-studies are independent, so they can finish at different times, and we do not have to read them all out at once. The design here is in RA. We have two doses. It is 120 patients total, a high dose, a low dose, and placebo, randomized one to one to one, so 40 on each. In PSA, it is 90 patients, two to one, 60 on drug, 30 on placebo. In ECSPA, the same, 75 patients, two to one, drug versus placebo. Across all three, these are placebo-controlled studies. We do expect them all to read out next year. We think kind of if we see those profiles that I described, quarterly, no meaningful safety issues and good efficacy, I think they're a leading product in the space. Got it. Would you then go directly into phase II, or do you need to do more phase II work? I think it all depends on the data. I think if we see compelling data, I think that we would be able to go to phase III with these designs. Of course, it depends if we see something that would be sufficiently compelling to move forward. Got it. I think you mentioned Roche, Merck, I think even Sanofi is going into other indication, is my understanding. Anything that we will hear from these companies that you are watching out for next year? Yeah. In addition to the three indications that we are doing and some competitors are pursuing as well, I think the other studies that are ongoing with TL1A are an SSc -ILD study, an HS study, an atopic derm study, and a MASH study. The timelines for those are, I think it's quite likely we could see one or two of those next year as well. Cumulatively, we may see four or five TL1A readouts next year. Got it. I mean, look, IBD in itself is very big, right? You have all these big indications. What is the eventual goal? You keep it with you? Are you monetizing this asset? What is the plan? Yeah. I think across these two studies that we're running, we're testing products that I think could be leading products in IBD and in rheumatic disease. Frankly, both sides are about the same. They're about $30 billion of commercial revenue across each of these sides of the business. I think we could have leading products in both of those spaces that we read out phase II data over the next year or so in. I think the opportunity is vast. I think the market opportunity would justify taking these products to phase III if we see those product profiles that we would expect. I think our decision will be kind of which ones do we think make the most sense for us to pursue. Could there be some that we choose to partner? I think that's absolutely part of the case as well. I really lay out what I think could be a very compelling set of products to take into phase III. Got it. I think I want to touch now a little bit on the bispecific side. I think there are, I mean, we all understand there are some nuances, some pros and cons with bispecific. How are you looking at the bispecific? Like how do they stack up? Where are you on the development timeline if you can put all of that in perspective? Sure. I think on the bispecific front, I think in general, if everything goes perfectly with the bispecific, I think it could match what we are doing with the co-formulations. However, I think there are quite substantial risks on the bispecifics that I do not think we face on the co-formulation side. The one maybe which is not a risk, I think it is a certainty that those will be one-to-one ratios of those in a bispecific, whereas our co-formulations do not have to be. In fact, we know in our phase II study, we are not using one-to-one ratios of these antibodies, and we think that that could be a more optimal approach. I think the other main risk with bispecifics is immunogenicity. I think that is particularly true with TL1A. We have seen more than a dozen TNF bispecifics that got made, and all of them got discontinued. I think that could be the case with TL1A bispecifics as well. I also think in general, bispecifics, when you're combining a membrane-bound target with a circulating target, especially if those are in different areas of the body, like alpha-4 beta-7 in the periphery combined with cytokines that will be in the inflamed tissue in the gut, I also think that's a pretty inelegant time to use a bispecific antibody. I think in general, the probability that they match us is quite low. I think the timelines are all a year plus behind us with one exception, which is the Roche bispecific where it's TL1A on one side and Stelara on the other, which I think is maybe not the optimal choice given that we know that the P19 inhibitors beat Stelara head-to-head in this population. Got it. You mentioned a little bit on the co-formulation. How did you come up with your, and what is, have you disclosed what is the optimal sort of? We have not shown the dosing yet in phase II. This is just for competitive and intellectual property reasons. We do know, and we just got our IL-23 data a week ago, and we are able to finalize our dosing now for all three of our targets. We know that none of them are one-to-one in terms of what we are dosing in the IBD setting. I see. Okay. Very good. Very interesting. Then just maybe quickly on the financials. I think there was a recent capital raise you did. Just how you are on the capitalization front? Yeah, sure. So we just raised another about $300 million, which puts our balance sheet nearly $800 million on the balance sheet after that financing, which takes us well more than a year beyond all of the readouts that we just talked about. The six readouts next year, followed by all the combination readouts, we have more than a year of cash beyond all of that. Okay. Sorry. One more question. Would you be required, just talk about the component contribution. How will you be establishing that? Yeah. The design of SKYLINE is to measure contribution of components. It is placebo against monotherapies, against combination. The intent is to show contribution of components in that study. Okay. You probably would have to do anything, let's say, head-to-head versus any of these three components? I think our expectation is that we would have to dose range our combinations after this. We haven't done that in this study. As to what we choose for our comparators in phase III, I actually think we'll have some choices. I think if we show head-to-head superiority over our monotherapies in this phase II study, I think we would beat almost anything on the market in a head-to-head study with our combinations. Very good, Cameron. I think that's all for you. Lots going on. It's a busy time. Plus readout from you. Then you also have the J&J readout, hopefully, like early next year that sort of clears the deck. Sounds good. Thank you. Thank you so much for the time.