Good morning, everyone. My name's Akash Tewari. I am a Pharma and Biotech analyst here at Jefferies. Day two of our beautiful healthcare conference. It's 40% over capacity this year, though, so we're hanging in there. Anyway, I have the pleasure of hosting Spyre, Cameron. Great to have you, as always. Why don't I give it to you for some brief intro remarks, and then we'll get started with some questions. Sure. Thanks, and thanks for having us. So just as a reminder, at Spyre, our focus is developing therapies for IBD that we think have a good probability of improving both the convenience of therapies, compared to what's on the market today, as well as we think driving a possibility of dramatically improving the efficacy compared to today's standard of care a nd our approach for doing that is taking forward a next-generation set of antibodies against the targets that we think are best in this space: Alpha-4 Beta-7, TL1A, and IL-23. We've engineered what we think are optimized antibodies against each of these, and we intend to develop them not just as monotherapies, but also as combinations. Yeah, and to that point, I think you recently announced that $200 million financing. I think, you know, there's obviously a lot of interest in the space. There's a lot of interest in your company. But you guys have been kind of aggressive about being in a really strong cash position. I think part of that is there's a lot of execution ahead. But can you talk about why, you know, you announced that now and really what you're going to do with that $200 million? Yeah, sure. So we announced the $200 million financing over the last day. The intent of that financing is to fund what we think is a very ambitious study that will kick off next year, which, as I mentioned, is testing all of our portfolio in a single platform study. We think this is the most efficient way to develop a portfolio of agents in this space, test three monotherapies all on a quarterly basis, we expect, and three combinations that we also plan to test on a quarterly basis. Really kind of a different profile than is being tested in this space. It's a large study, and this financing enables us to read out all six of those readouts. Really, we think potentially paradigm-changing products in this single study. and this financing lets us have the capital to execute on that study and really not take any slowdowns between that now and then. Understood. And, actually, we should hit on that a bit. Talk to me about why you chose to go with that development path. And then number two, how does that actually accelerate your time onto the market with novel combo strategies? That's right. So, what, so why a single study with all of these agents? So to develop a combination, we have to demonstrate the contribution of components, meaning that our combinations are superior to our monotherapies, and our monotherapies are superior to placebo. It's, we have three potential combinations in our portfolio. It's certainly possible that we could run three separate combination studies, one for each combination, where it would then need three placebos, and we would need to duplicate every monotherapy arm. By doing it in a single platform study, we have only a single placebo arm. We use each monotherapy once, and then we get three combinations in the same study. Overall, it's about 40% cheaper overall. It also allows us to activate sites only once. As you're probably familiar, enrolling IBD studies is not trivial. It does take a long time to get sites activated across the globe. By having a single platform study, we can start this study with our Alpha-4 Beta-7 agent against placebo next year, start activating sites, and then add our TL1A and IL-23 programs to the same study. It's a much more efficient approach overall. Understood. And maybe to put a finer point on that, by going with the novel combo strategy now, you're probably cutting two years from your development path on if, you know, if you did this stuff sequentially. Is that a fair read? I think at least. Understood. Now, there are also, you know, things that you have to do from the FDA perspective in order to allow novel drug-drug combos like this to get put into place. Talk to me about your understanding about the regulatory path, and then also maybe whether it's clinical or preclinical work that your team has internally that makes you confident that you can execute on this? That's right. So, one of the things that you'll notice, kind of across our portfolio, we are getting open INDs for all of these programs. Sometimes it's faster to execute phase I studies outside the U.S., but we think it's important for our portfolio to have kind of ex-U.S. approval to get going as quickly as possible, but then open INDs so that we have plenty of feedback regarding not just the design of our phase I studies for each of these molecules, but also all the preclinical work to enable not just these phase Is, but the combo study to follow. So in particular, of course, we're doing IND-enabling tox research of our programs. We're doing chronic tox research of our programs. We're also, and you can see that we're executing combination tox research of our combos as well. Show some data in our corporate slides that demonstrate that we're dosing both of these agents. Right. And NHPs together. It's a 90-day combo tox study that we believe is necessary to execute the phase II. Cameron, you said something interesting. I don't think a lot of investors appreciate that. A lot of the small-cap companies I talk to, they're very much focused on the U.S. market. You know, we want to get regulatory path there, and then ex-U.S. will kind of figure it out as we go along. You guys are making, you know, putting in place a regulatory pathway now in order to get ex-U.S. approval. And it almost seems like there's like a pharma development plan. Talk to me about the importance of, you know, the groundwork of an ex-U.S. development plan. Why is your team being so aggressive on that? Ultimately, this is a large global market. I mean, it's a $20 billion market growing to $30 billion by the end of the decade. Kind of the size of the IBD market outside the U.S. is huge, and so is the opportunity to enroll patients in our clinical studies. So, I mean, the study that we're anticipating to start next year, we expect to be 500 patients globally. We expect to have sites across the globe to execute on that study. We've also shown now that we're adding ethnobridging cohorts in our phase I studies to explore the PK of our drugs, not just in individual Caucasian individuals, but individuals of other descents as well. So we really are enabling the ability to run a global program here. We think it is necessary to enroll this study correctly and enroll a representative population that we can then move forward to a pivotal study straight after this. Understood. Now, maybe stepping back, and you, you had data with your, you know, long-acting Entyvio. There's a lot of discussion about, okay, these are long-acting drugs, but then there's also the efficacy angle. Talk to me about what you've seen in terms of dose response with Entyvio historically, particularly in the induction stage. Could we actually see meaningfully better efficacy with your compound if you can get higher exposures? Yeah, sure. The data for vedolizumab comes from really two sets of data. The first would be their pivotal studies. In the GEMINI studies, there was a clear exposure response that was identified in that study. Takeda published on those. It was also highlighted in the FDA's review, in the ClinPharm review in the BLA. They highlighted this relationship where the individuals in the higher exposure quartiles of vedolizumab had substantially higher clinical remission rates than those in the lower quartiles of exposure. This has been replicated in the real world, too. So, now we have thousands of patients that have had vedolizumab in the real world, and these large publications showing a very similar relationship, that patients that have greater exposure have a higher probability of clinical remission. In that BLA review, the FDA actually directly suggested testing a higher dose. And given that SPY001, our first molecule, has the same epitope and very similar potency to vedolizumab, we think that's the right thing to do with this molecule, is to test a higher coverage of this target during the induction phase where this steep relationship is shown. With the phase I data that we reported last week, we think this is easily achievable with two IV loading doses. We're aiming to target all patients into that fourth quartile of exposure where vedolizumab maximizes efficacy. And we do think there's an opportunity to improve on efficacy there. And one kind of just a side point there is, how are we sure that the safety of that is going to be fine? Right. vedolizumab has dosed two and a half fold their commercial dose. It's a 300-milligram dose commercially, but they've dosed 750 milligrams in safety studies. We know in the real world that physicians frequently use vedolizumab more often to get greater exposure as well because they believe that they can capture greater efficacy. Understood. Now, you had your healthy volunteer readout, and the half-life was even. I mean, it was better than our models were projecting. I mean, I think you look at IL-23, you expect that to have a very strong half-life. Entyvio, I think you had shown encouraging half-life in non-human primates, but what we saw actually in humans was, I think, surprising for us internally. And I felt like it was almost surprising for your team. But talk to me about how the flexibility on dose actually translates into because I think what we want is, you know, what the market would want is a nice 2 mL, you know, dual-chamber auto-injector type of formulation. Yep. You know, talk me through the dose response you showed and why you feel confident that actually might be possible with either a quarterly or six-month regimen? Yeah. So just to remind everyone what we had known before our data last week, which is that we had the shortest half-life of all of our molecules in non-human primates. Our Alpha-4 had a 22-day half-life in NHPs versus 24 for our TL1As and 30 for our IL-23. So going into those data, we expected our Alpha-4 to be our dose-limiting molecule for not just monotherapies, but our combinations as well. We were substantially surprised by the half-life that we saw for our Alpha-4 molecule, greater than 90 days in the lowest cohort, more than 100 in the second cohort, that we think, and we show our phase II projected doses, with a single shot, we can cover the levels of exposure that vedolizumab has on a dose every two weeks. We can do it twice a year. So this, this half-life extension, approximately four-fold compared to vedolizumab. Plus, we've developed really high-concentration SubQ formulations here. We have a 180 mg per mL formulation of this molecule. Means in a 2 ml auto-injector, we can put 360 milligrams of this drug. It's more than enough to cover the exposures that we need on a twice-annual basis. You know, two shots a year versus 26, we think, is a meaningful convenience improvement. Understood. Now, I guess one of your, the sister Paragon companies that has an IL-23, and I think they've shown data, and talked about the potential for biannual to even yearly dosing. I mean, I think you have 30-day half-life on the IL-23 preclinically. So that seems like the natural combo target here. When we think about the dosing possibilities, why should my mind not go into yearly combinations? And if not, either biannual or yearly combinations with your Entyvio and IL-23 combination? Yeah. So I think a couple points. So one, the doses required of these mechanisms in IBD is not the same as it is in psoriasis and dermatologic conditions. I think there's evidence from multiple mechanisms that you need substantially more drug in IBD than you do in psoriasis. That's, I think, most known for the IL-23 class, which is exactly what we're talking about. So I do think we will need more drug in the IBD indications than you may need in psoriasis. So I think that's kind of the main driver of this. And then second, because of the combination approach, it is whatever is limiting our dosing will determine the dosing of our combos. I think at this point, we have high confidence that we can dose our Alpha-4 on a twice-annual basis. Betting today, I would think that we probably do have a high probability of dosing our IL-23 on a twice-annual basis as well. The TL1A is probably the toughest now. Right. After the data that we've shown for Alpha-4, the TL1A will be the most challenging to dose on a twice-annual basis, but we're advancing two molecules in parallel phase I studies. Both will start in the next few weeks here. Both will have data in the first half of next year. We have two shots at the possibility of having a TL1A that we can dose on a twice-annual basis. You know, that's usually, I don't think you always see that with small-cap biotech companies advancing two products forward with the same target. Talk to me about the potency differences between both of those and then what your base case expectations are for dosing intervals in healthy volunteers. Yeah. So just the rationale for why we took two. We know TL1A can be an immunogenic target. We've seen that with prior TL1A molecules that they can have high rates of ADAs, and that's from multiple sponsors. We've seen TL1As that had that. Immunogenicity is something that can be hard to de-risk preclinically. So we thought we had a development campaign here that was very broad, identified a large number of antibodies with excellent properties, extended half-lives, great potency and selectivity, and we thought the rational thing to do was to advance two, at least into tox. And then, in both tox studies, we had the top dose was the NOAEL. So no tox observed. And again, we think the rational thing to do is advance both into phase I. I think our expectation, we saw a 24-day half-life in non-human primates. We need about a 40-day half-life to dose it quarterly. We need about a 65-day half-life to dose it twice annually. Those are within the range of what we think should be achievable with YTE antibodies, and we have two shots at it. I think it's a reasonable probability. We also think something that is very interesting with the TL1A is the opportunities outside IBD. The strategy of having two of these provides us quite a bit of an optionality in terms of thinking about these molecules both in use in the combo study that we've described, but also potentially a set of large indications where TL1A is implicated. We think having a quarterly version of a TL1A or twice annually would be the most attractive TL1A in those additional indications as well. Understood. I mean, it almost sounds like you're talking about systemic sclerosis or some of the other indications where TL1A is, and you could have probably different pricing strategies there. Outside of the kind of, you know, Humira and IL-23 indications where TL1A is going, talk to me about the other maybe more high-priced orphan indications where they're shown at least preclinical biological rationale. Yeah. So, so there's about 15 different indications where TL1A is implicated, either genetically or with animal data or human tissue samples suggesting that TL1A is a, is a disease driver in a variety of indications. These diseases range from low single-digit billion market opportunities to tens of billion market opportunities. I think we and most of the other TL1A sponsors are going to hold our cards close to our chest on which ones we think are most attractive, until we're ready to launch those studies, because it's going to be a very competitive space. But I think if we have quarterly or twice-annual TL1As with the, the potency that we've shown, I think they would be a very attractive molecule in those indications, too. Understood. Maybe just stepping back and talking about TL1A. I mean, it was, it's emerged, I mean, the TNF superfamily target, it's emerged as a high-quality target. But there's been differentiation, at least in my opinion, with some of these molecules, right? If you look at the Roivant- Pfizer potent molecule, probably some issues with viscosity in terms of getting SubQ. When I look at the Teva- Sanofi molecule, very short half-life, in my opinion. Even when I look at the Merck molecule, there are, you know, it's funny, everyone criticized the Pfizer biomarker strategy, but when we saw recent data at UEGW, it actually seemed like the Merck biomarker was degrading more rapidly than what we saw with Pfizer. So I'll give you a broad-based question. From the molecules you've seen so far, how do you kind of rank order them from a competitive threat perspective? And then when you look at your compounds, how do you feel like they could actually differentiate, given that they are behind? Yep. So there's, in contrast to our Alpha-4 and IL-23 programs where we thought vedolizumab was an excellent molecule to optimize around, and risankizumab was a great molecule to optimize around for our IL-23, we didn't choose to do that for our TL1As. So, I mean, you can see that we chose very distinct epitopes. We have demonstrably different potency, meaningfully extended half-lives. We have 200 mg per mL formulations of both of our TL1As as well. So no viscosity issue either. We didn't choose any of the three ahead of us to say, "Hey, that's perfect, and we want to make a better version of that." and you highlighted the issues. The Prometheus molecule had relatively low potency. The Roivant molecule had immunogenicity concerns as well as inability to formulate at high concentration. And the Teva molecule has a very short half-life that makes dosing monthly pretty tricky. We think that ours have kind of all of the properties that we would look for, and we have two of them advancing in parallel. So we think it's a high probability that we'll have a great one coming out of phase I that we think should be attractive in IBD and also outside of IBD. Understood and outside of just the quality of the molecule, what about the biomarker? Sure. Right? Because I think with Pfizer, you know, they said, "Oh, they actually have to do biopsies." Prometheus was supposed to be an easy, you know, an easier-administered one. I know your team's been developing your own proprietary one. What's going on there? That's right. So we, we've partnered with one of the largest IBD biobanks that has tens of thousands of IBD patients who have been fully sequenced. So their genetics are fully characterized, proteomics characterized as well. Many of these patients have received the targets that we're looking on, vedolizumab and IL-12 or IL-12/23 targeting agents. And that provides a lot of information about responders and non-responders and the profile of those patients, relative to whether the drugs worked for them or not, which is, frankly, a lot more information than was had when the TL1A selection strategies were developed, given that there are not commercial TL1As available. So we believe there are opportunities not just to develop more powerful selection tools for TL1A. There are relatively simple strategies that were used for the first-generation selection strategies. And then nothing has been demonstrated yet for Alpha-4 Beta-7 or IL-23. And given the data set that exists now for responders and non-responders in these populations, we think it's reasonable to test that as well. Understood. So not just for TL1A, but also for your other? We think there's no reason that you shouldn't use a similar approach for all three targets. From a proteomics perspective, I mean, could you kind of, and you've seen this in oncology where it's actually dual targeting, where you're not just looking at one lens, but you put both lenses where it's, "Hey, signal for high response to IL-23 and signal for high response to TL1A." Are you able to actually look at dual targeting biomarkers here? Yeah. I think we've had a lot of conversations about whether we'll use the same strategy for our combinations versus our monotherapies. And the answer is we'll see. I think we don't have any patients out there certainly that are receiving Alpha-4 and IL-23 agents together. So we don't have that type of information for responders and non-responders. But for each of these targets, there actually are pharmacogenomic mimics. There are genetic variants that mimic the activities of these drugs as well. So there's a reasonable strategy to use those genetic mimics of the drugs to identify who might be more likely to respond or not. When does that biomarker approach start getting implemented? Could that be in that platform phase II study you're talking about for next year? That's our intention. I mean, we're not planning to run a selection strategy for who enrolls in that study. Right. I think kind of like the previous sponsors in this space, the right thing to do is enroll all comers, but then pre-specify for each of the arms which subgroups we think might be the hyper-responders. Cameron, and it's funny, I, I'm frustrated when I talk to Merck about this angle because they never feel like they haven't committed. Is it the biomarker strategy? Is it the all-comer strategy? Do you feel like the biomarker approach might be the right strategy for some of the more high-priced orphan indications? Or do you feel like, no, this is going to be something we'll be employing across the board for even some of the larger I&I indications that you're going after? Yeah. I think when we think about, we'll start with the IBD population. I think it's fair to think about this population as individuals. Their disease is unlikely driven by a single pathway for each individual. It's almost certainly true that multiple pathways are driving the disease and different levels of each pathway is driving the disease in different individuals. So a selection strategy can certainly enhance response rates, but we think the combination strategy also offers an ability if certain individuals, their disease is driven by two pathways, that's where you're going to see a combination effect is dramatic as well. So I think a platform study like this really provides a huge amount of information for us, not just on, okay, where do our monotherapies work best and can we identify individuals where all they need is a monotherapy. Right. Or can we identify individuals where it truly is necessary to have a combination and you see a VEGA-like response where they doubled the efficacy in an all-comer population? Understood. Now, just lastly on TL1A, you know, I think it is the shiny new toy right now. There isn't a lot of long-term follow-up data. It is a TNF superfamily indication. I've noticed with your team, you know, when you're thinking about combinations, the first combo you've talked about is IL-23 with the Entyvio. It's not TL1A. And part of me thinks you're also waiting to see how safety plays out because it seems like a critical component of your combination strategy is we want to deliver best-in-class efficacy, but we don't want a black box warning. You've seen more long-term data from the TL1A class now. Where do you kind of stand on the long-term safety with TL1A and the risk of severe infection showing up over time? Yeah. I agree with you and kind of I think we highlight that specific combination for a reason. It's actually driven by many of our SAB members and KOLs that highlight to us. If they had to pick what they thought would be the safest possible combination to test, it would be Alpha-4 and IL-23 as the two agents that are on the market that they have a huge amount of experience with that do not have meaningful safety risk, no black box warnings, no meaningful monitoring requirements either. TL1A potentially has the greatest efficacy as a monotherapy, but I think appropriately point out we don't have the phase III data sets yet. I think the safety data so far looks quite good, though. I don't think there's a meaningful difference in infection rates that we've seen with TL1As yet. Those studies were also done during COVID as well. So I think it is important to recognize that too. But I think so far it looks like greater efficacy and cleaner safety than TNF, but it's early. So I think we'll continue to monitor it. Understood. Now, going into, you know, again, the novel drug-drug combo, sounds like preclinical data, if you don't have overlapping toxicity, you're fine. But, you know, I feel like this draft guidance is almost purposely written in a vague way. You know, so how do you interpret overlapping toxicity? What does that actually mean? If you have, you know, one or two different AEs that show up in combination that might just be background noise, does that suddenly mean that you can't run a novel drug-drug combo? I mean, you're going to start generating human data. So for the investor community, how should we think about the data set you'd have to show to make you feel comfortable you're not showing overlapping tox? Yeah. So I think at this point we've said that we have the top dose in both of our O1 and O2 IND-enabling tox. We observed no tox. It was the top dose tested. So I think in terms of can there be overlapping tox when two of your three molecules have no tox? Even if the third one did, you couldn't have overlapping tox with the other two at this point. That said, we are running the combination tox already to kind of really rule out the risk that you see something that is not seen for either of the monotherapies. It's only seen in combos. We think the right thing to do is just do this proactively. Right. So we're running the combo tox studies. Understood. Maybe just lastly, and we've talked about this in the past, again, you know, there's a very big difference between biologic experience and then naive patients. You know, I think everyone looks at VEGA and they say, "Oh, great, this is going to be additive efficacy." That's not the case in a lot of, you know, if you look at historical studies with methotrexate with a biologic in a refractory setting, you don't see additive efficacy. It can be a little more modest. I think, and this is the question we kind of asked you on the call too, you know, if one plus one doesn't equal two, what if one plus one equals 1.3, 1.5? What do you need to show in your combination approaches to really justify moving forward? Is it fair to say even if you have, let's say, 5%, 10%, 20% higher efficacy and you don't have a toxicity profile, that should justify the combination strategy moving forward? And then number two, you know, I'll ask you in terms of DUET and what's going to happen with J&J, how do you think that's going, how do you think that's going to play out in the naive population versus the biologically experienced population? Yeah. A lot of, a lot of good questions in there. I mean, I think from maybe from the DUET expectations first, I mean, I think you highlighted the difference. It's an all-refractory population. It's a bit of a unique development program where VEGA was all naive and DUET is all refractory population. Our plan is to run a study that is a mix of the two. So I think the realistic answer is that you will have to blend the results to see what you expect in terms of a 50/50 mix between naive and refractory. I do not expect to see a 47% clinical remission rate in a refractory population. I also don't expect to see monotherapy remission rates in the mid-20s either. I think we'll see the monotherapies come down. We know that into kind of the low teens likelihood for each of the monotherapies. And I would very much expect that the combination is not going to be 47 either. Does it have to be double? I don't really think so either. I think a clinically meaningful difference if you don't see a safety detriment and these are developed as a single product that is priced like a single product, which I think J&J has the ability to do. It's a co-formulated product. And I think we have the ability to do. These will be co-formulated products that we move forward. They should be priced like a single drug. They shouldn't be priced like two drugs put together. Yeah. I think if you had better efficacy, no difference in safety, and a similar price point, that's a better product. Maybe just lastly, just, and I know we're out of time, but I want to stick this in. The nuance of the mechanisms of action, because, you know, I, I think that gets lost. We just look at VEGA and say, "Okay, that's going to be the mandate on what combination strategies are going to be in these GI, I&I conditions." I'm not sure you guys agree with that. Talk to me about the approaches you're taking and how you might have more synergistic efficacy rather than the approach J&J is taking with the TNF. Yeah. I typically think about as many aspects of evidence that we can to justify these combinations. I typically start with human genetics because that's my background. And we know for all three of these targets that kind of there is evidence of single agents contributing to IBD pathogenesis and two agents together making individuals more likely. So there's genetic, human genetic evidence that two pathways contribute. There's plenty of animal data suggesting across all three of these mechanisms that kind of there's additive or synergistic depending on which model you look at. And then there's cell-based studies as well that suggest the same thing. I also think kind of when I look at the VEGA result and think, "Okay, TNF and IL-23 works pretty well." TL1A is in the same superfamily as TNF. That's a very logical swap given the data we have today on TL1A versus TNF. Agreed. I also think replacing TNF with Alpha-4, Beta-7 in UC also makes a lot of sense given that we know in the VARSITY study that Alpha-4 Beta-7 beats TNF head-to-head in this population. So I think all of these are good reasons why these combos should work. We are out of time, but I really enjoyed it as always. Thank you so much, everyone.