Spyre Therapeutics, Inc. (SYRE) Earnings Call Transcript & Summary

Tyler Van Buren here, senior biotech analyst at TD Cowen. Thank you very much for joining TD Cowen's 46th Annual Healthcare Conference. Saving the best for last year with the final company slot of the day. Very excited to have a hybrid presentation and fireside chat with Spyre Therapeutics. It's my pleasure to introduce Cameron Turtle, CEO of Spyre as well as Joshua Friedman, Senior Vice President of Clinical Development. Cam and Josh, thank you very much for joining me. Cam, I'll hand it over to you.

All right. Thank you, Tyler, and thanks for hosting what has always been a great conference. Before we start, just quick disclosures here. I'll make some forward-looking statements. These are subject to the normal risks and uncertainties for a biotech company. Overall, our goal with Spyre is to deliver what we hope to be indication-leading products across autoimmune diseases where we still see substantial unmet need on the market today. On the inflammatory bowel disease side, we're starting initially with monotherapies against what we see as the best biologic targets in this space. This is Alpha-4-beta-7, the same target as ENTYVIO, TL1A, where we've seen 3 very successful proof-of-concept studies and IL-23, the same target as risankizumab or Skyrizi. We think that our antibodies here have engineered for improved properties relative to first-generation molecules, which we think are exciting in and of themselves as a step forward in the field to substantially improve convenience and potentially improve efficacy over first-generation monotherapies. But -- and we think these could be actually the leading products on the market today in inflammatory bowel disease. However, we don't think that the future of IBD looks very much like the standard of care today. In particular, we, and I think everyone who's very serious about the future of IBD is investing in combination therapies. And the premise here is relatively straightforward that this is a heterogeneous disease. It's a multifactorial disease where numerous pathways are involved in driving the pathogenesis of IBD, and it's very likely that blocking more than one pathway is going to lead to additive efficacy. Simply put, we think that having the best components is likely to lead to the best combinations, and we have engineered the optimized versions of each of these monotherapies and are combining them in pairwise combinations. Outside of IBD, we've expanded the strategy to explore rheumatic disease as well. I think we and others who have invested in TL1A believe this product has a pipeline in a product potential where we could see that it has efficacy in a range of autoimmune diseases. And we've been moving quickly here, and we actually have the potential to be first and best-in-class in this basket of rheumatic diseases in RA, psoriatic arthritis and axial spondyloarthritis. Across the 2 of these programs that we're running, one in the Skyline study in inflammatory bowel disease and second in the SKYWAY study in rheumatic disease, we plan to deliver 6 Phase II proof-of-concept readouts this year on the IBD side beginning next quarter. And then towards the fourth quarter of the year, we expect to read out all 4 proof-of-concept readout -- all 3 proof-of-concept readouts in a placebo-controlled setting. To go just a brief background on these molecules themselves. Over the last 1.5 years or so, we've shown in Phase I studies that these molecules roughly have the properties that we expect. So against each of these targets, we believe these molecules have the same or improved potency compared to the first-generation molecules. And then in Phase I studies, we showed that each of them has more than 3x the half-life of the first-generation molecules. And we've engineered each of them as well as the co-formulations of each of these at high concentrations at 200 mg per ml and the ability to inject these in 2 ml auto-injectors, which provides an incredible convenience profile for patients looking at 2 to 4 doses per year, which is a major step forward relative to existing products on the market today. So overall, what we're trying to achieve here on the inflammatory bowel disease side. Here, we're showing the standard of care today in terms of dosing on a monthly cadence with efficacy that certainly leads quite a bit to be desired. We expect our monotherapies to move this out to the right here in terms of dosing on a 2 to 4x a year basis, potentially with improved efficacy or in a similar range as the existing products, whereas our combinations, we expect to be potentially adjusting the treatment paradigm completely. This is a disease where physicians are looking for top-down therapy, meaning the best product comes first. And we think that these combinations have the potential to be that product and dramatically change how this disease treated. On the rheumatic disease side, we see a similar situation that despite numerous product classes approved across these 3 indications we're testing, most of them are still delivered on a pretty inconvenient basis, and most patients don't get into long-term remission with any of the existing therapies. We expect TL1A to be an important addition to this market as well with the potential to deliver a far more convenient product profile than what's on the market today. So digging into the inflammatory bowel disease strategy in a bit more detail. This is a summary of the existing approved classes in IBD. And I think the Y-axis here makes it clear why we see the unmet need despite a huge amount of progress in this field, we still see what the physicians refer to as a therapeutic ceiling in this space. On a placebo-adjusted basis, we don't get above about 25% clinical remission with any individual mechanism, which leads to patients having to cycle through many mechanisms, often losing response or remission to the drugs that they're on and suffering what can be very serious consequences of this disease, which can include surgeries, hospitalizations, as serious as having parts of the GI tract removed and having to live with serious consequences for the rest of their lives. The potential for combinations to break this therapeutic ceiling was shown most obviously in the VEGA trial that J&J released just a couple of years ago, where they combined the only 2 drugs that they have, golimumab, an anti-TNF agent with guselkumab, an anti-23 agent. And what they saw is remarkable, really a doubling of effect size in these frontline patients, a 47% clinical remission rate that is dramatically beyond what has been seen previously. Despite kind of this excellent result, we think it's quite unlikely that this is the combination that will dominate this field for the long run. In particular, we think that replacing an anti-TNF therapy, particularly golimumab with either an optimized Alpha-4-beta-7 or an optimized anti-IL-23 is likely to be a superior combination. This is based on the fact that in these indications, we've seen head-to-head superiority of Alpha-4-beta-7 against TNF. In fact, this is kind of a TNF that has been shown to be kind of more efficacious than the golimumab agent. And vedolizumab, anti-integrated anti-alpha-4 agent was shown to be head-to-head superior on efficacy in the VARSITY study, and it also had a superior safety profile. In addition, we've seen 3 Phase II TL1A studies, so they weren't conducted head-to-head against TNF. I think any reasonable cross-trial comparison of the results for the anti-TL1A mechanisms would suggest that this is a superior agent in terms of both efficacy and safety relative to TNF. So with our combos here, we're replacing kind of the TNF component with something that has been shown to be superior or is likely superior, and we think it is quite likely that our combinations will deliver a superior result in that combination that's already been shown. So how we're advancing this is in what we believe is a very efficient Phase II approach, where we're testing all of these agents, both as monotherapies and in combinations in a single platform study. The advantage here is that we get to activate sites once and geographies once and continue to add additional agents to the study. In addition, we don't have to enroll 6 different placebo arms to investigate each of our agents and can use the placebo as comparator for each of our arms as well as our monotherapies as comparisons for our combinations. So this study has been ongoing since the middle of last year. We finished enrolling the Alpha-4-beta-7 cohorts and are making great progress on the other 2 monotherapy cohorts enrolling well ahead of schedule. We expect to start reading out these data next quarter, initially from this Part A portion, we'll be looking initially at objective measures, including a change in histology index, change in endoscopy scores as well, as well as more standard endpoints that we'll use as primary endpoints in Phase II and beyond, such as clinical remission. As soon as we finish screening for Part A of the study in the open-label monotherapy cohort, we'll immediately pivot into Part B. So by the time we read out these Part A cohorts, we'll have already been enrolling the Part B cohorts for a number of months. So with that, I'm going to pause here and turn it over to Dr. Friedman, who will walk through our strategy in rheumatic disease.

Thanks, Cameron. So let's take a look at rheumatic disease. Similar slide to what Cameron showed earlier for IBD, demonstrating the unmet medical need in this space. As you can see, the unmet medical need comprises both a high prevalence with over 3 million patients across these 3 rheumatic diseases in the United States alone. And again, a ceiling on efficacy across these mechanisms. And we call it a ceiling. But of course, if the ceiling in this room were down here, we'd all be quite uncomfortable. And unfortunately, that's how the patients find themselves. And they're also not ideal in terms of dosing frequency with dosing frequencies monthly, every 2 weeks, every week, which we think we can do better for our patients. And there are also safety concerns. If you look, for example, at the drugs available for RA, all but one of them has a black box warning. And so what happens when you put all this together is that patients end up cycling through drugs either because they didn't hit the efficacy they needed at the outset or they had some efficacy and then they lost it over time because the drugs aren't durable enough. So there's definitely room to improve on this for our patients. So we recognize that there's potential for this mechanism, of course, in IBD, and we've already mentioned rheumatic disease, but actually, there's a potential for a range of diseases. And I think that this potential for a portfolio and a product is what drove the very high valuation M&A for this target in the recent years. And there's good scientific basis for a lot of them, but we prioritize rheumatic disease after IBD. So some of the evidence driving that decision for us begins with the most basic thing of all, which is, is the target elevated in the disease. And we're just showing you a little bit of the data on that front, which showing elevated gene expression in the blood for TL1A across all 3 of those rheumatic diseases. But there's also translational data showing that the protein is elevated in synovial fluid, which is closer to where the site of action is for the disease. And so it's quite clear that this molecule is present at the scene of the crime for the diseases. But it doesn't establish causality. But there's evidence there as well because at the genetic level, we know that there are variants in the TL1A gene that are associated with increased risk across these diseases. And so that's a strong clue pointing towards efficacy. And there's also preclinical models, which is one of the only things you can do short of a clinical trial to establish efficacy. And we and others have found that blocking TL1A can prevent or ameliorate both arthritis and psoriasis in animal models. And finally, one other piece of evidence that we sort of intimated, which is that there's already proof of concept in inflammatory bowel disease. And that we know shares mechanisms at the level of cell types like Th1 and Th17 cells and molecular pathways as demonstrated by the mechanisms of action that work across those 2 diseases. So plenty of reason to believe that this is an effective mechanism in these diseases. So this is how we're going to test that hypothesis. We have -- again, we're taking advantage of an efficient trial design, in this case, a basket trial with 1 drug, 3 diseases, and we get efficiencies from using the same sites, same contracts across all 3. There are 3 independent substudies with the key inclusion and endpoints as shown here with 2 dose levels in RA, the high dose level in the other 2 indications. Each one is enrolling independently and well, and each one can read out on its own or they can read out together just depending on the timing. With that, I'll turn it back to Cameron.

And I'll just do the last slide from here. I don't have to stand up again. So in short, I think it will be a very interesting next 18 months for the company here. We'll start by reading out those monotherapies in IBD starting next quarter, finish the year by reading out the placebo-controlled readouts in rheumatic disease. And then as we turn the calendar into '27, you should expect maintenance data from each of those studies as well on the order of 9 to 12 months after each of the induction data sets. And then, of course, the placebo-controlled Part B portion of the Skyline study, where we'll see monotherapies against the combinations against placebo in ulcerative colitis. So altogether, we think it's an incredibly transformational next 2 years for the company, and we're very well funded to undertake this effort with about $750 million on the balance sheet as of the last quarter, more than enough to fund all of this and a year beyond each of these readouts. So I think that's it for the presentation portion, and we'll turn it over to Q&A.

Great. Thanks very much for the presentations, Cam and Josh. Pretty exciting catalyst calendar on that last slide. We'll start with the Phase II Skyway UC study, of course, naturally. So Spyre-1 monotherapy cohort, again, complete enrollment, first data readout expected next quarter. I guess 2 follow shortly thereafter, maybe Q2 depending on enrollment. And then definitely not 3, but 3 will come at some point after 2, clearly. So just, I guess, for all 3 of these readouts, we're kind of should set expectations similar for all 3 readouts to some extent, right? And what is the expectation in terms of monotherapy efficacy based upon the patients you enrolled and I guess, safety as well?

Yes, sure. So none of these are first-in-class molecules. We're all kind of -- we have first-generation molecules against each of these. And I think a fair initial assumption is that each of our molecules will behave like the first-generation molecules in terms of safety and efficacy with the primary differentiation being the dosing interval that we talked about. I think that's a reasonable base case. I think there is a potential upside with a few of these mechanisms that there might have been underdosing with some of these mechanisms. So in particular, the ones that I would highlight, I think on Alpha-4-beta-7, we've seen that. So in terms of the vedolizumab data in both the GEMINI studies and in the real world, we see that patients that have higher drug exposures tend to have higher rates of [indiscernible] and so with our high doses in the Skyline study, we are testing that. We are testing whether a higher exposure against each of these targets could lead to greater efficacy. I also think that might be possible as well with the TL1A class, particularly in the maintenance setting, where I think we've seen both dose responses and even some sponsors choose to increase their dosing frequency as they went from Phase II to Phase III, suggesting that full efficacy might not have been captured in the maintenance setting for TL1A. So that's really, I think, the bar for all 3 of these mechanisms is really behaving like the first-generation products. We think it's -- we think the difference in efficacy that we're likely to get with this dosing is likely smaller than what we expect to see when we dose these together as formation.

Great. And is the goal really quarterly? Or are you thinking about potentially going beyond that in terms of duration? And will we be able to answer that question with these monotherapy readouts potentially?

Yes. So I think the maintenance data really is intended to answer that question. So we are testing both a quarterly dosing interval as well as a twice annual dosing interval in this trial. So we will see not with the induction data that we plan to report this year, but as we get into the maintenance readouts next year, certainly, the low doses that are looking at that longer twice annual dosing interval will examine whether we can dose this that infrequently.

So moving to the combos. So DUET data at DDW in May, potentially, hopefully, I guess, how confident are you that we will get the data then? And how should we think about expectations for remission rates in this readout, especially given the patients that they enrolled?

Yes. So I think I'm done guessing at when will see the DUET data at this point. I think we were originally supposed to see it in the middle of last year, and that kind of has continually been postponed. But the 1 year from them having the data is in the middle of May of this year. So on that time frame, we will see it posted if it's not announced beforehand. But there is a big gastroenterology conference in early May in Chicago at the DDW conference, and so that would be a very logical place for it to be announced. In terms of what we're expecting, I think there's been maybe some controversy around this trial for the last few quarters because they've had these data and they haven't been announcing it. In some ways, I think that controversy has somewhat been relieved over the last couple of months as J&J has made it clear that they're advancing that combination to Phase III. They're calling it the future treatment of choice for refractory patients in IBD and a future blockbuster. So they're the only ones that have seen the data in the refractory setting. But if they're excited about advancing it particularly in that setting, I think we largely know that, that worked. I think it bodes very well for the combination approach overall if the J&J combination worked. And what I mean by that is, as I mentioned in the prepared remarks, that this combination that includes golimumab which as much as that's a great agent, it is not the best of the TNF agents in terms of commercial use or in terms of the efficacy data that's been generated in IBD with that molecule. And the design of the DUET study is that every patient in that study is a refractory patient, meaning they failed an existing biologic. And in most of the world, the first or second-line agent is going to be an anti-TNF therapy, and it's likely to be infliximab or adalimumab, which, in fact, have better data than golimumab. And so if a combination using a TNF component works in a population that has failed a more effective TNF component, I think the setup that we have where not only are we replacing the TNF with a component that is superior in Alpha-4-beta-7 or TL1A, but then we're also testing our combinations in a population that have not failed our components for the most part. I think that setup is -- bodes well. And I think it's quite likely that if the J&J product was a success, I think ours are set up for even more success.

What do you think is the minimum increase in remission rate in this refractory population that KOLs would like to see to gain further confidence that is, I guess, supporting what J&J has been saying over the last few months?

So I think we actually have a pretty good set of precedents in IBD for what it takes to shift the treatment paradigm. And we have, I would say, 3 head-to-head trials over the last few years that have led to the biggest mega blockbusters in this space. So we referenced one of them, ENTYVIO beating HUMIRA. That was actually just under 10 percentage points of clinical remission and has led to ENTYVIO being a $6-plus billion drug today, kind of high single-digit peak is the expectation there and a similar delta that was observed for the 2 p19s that showed superiority over STELARA, Skyrizi and TREMFYA with now both AbbVie and J&J guiding to those products being high single-digit billions of sales in IBD. So I think this 10 percentage points of clinical remission delta for products over the existing standard of care is clinically meaningful. And if those products don't have a safety downside, and I think if they're priced like a single drug, which is my expectation for these combinations, I think they will be used first. It is a superior product, and I expect that treatment paradigm to shift rapidly to those products that have a better profile.

And we'll get the DUET data, hopefully, again, eventually. You mentioned the VEGA data. Are there any other historical combination data sets that really give you confidence in the combination approach?

Yes. I mean, certainly, the VEGA study was the foundation for us. But I think that there's more evidence. I mean, although it's outside of IBD, the AFFINITY study is also quite meaningful to our minds. That was in PSA, also from J&J. Same combination of anti-TNF and anti-IL-23. But in this case, it was in a refractory population. In fact, 100% of the population was already TNF refractory. And yet when they added golimumab on top of anti-IL-23 guselkumab, they found numerically improved -- numerically pretty significant improvement across most of their endpoints. So that gives us the first clue to what we might see in a more refractory population, including an [ ID ]. In addition to that, there's a pretty good substantial body of evidence of case reports from gastroenterologists who are struggling with their most refractory patients. They try combos and then they report them. In fact, there even reports collating all of those reports. And in those cases, they're seeing greater efficacy and not much of a safety signal. And then even most recently, at the ECHO conference just last month, there's Takeda-sponsored study where Alpha-4-beta-7, ENTYVIO was combined with a JAK inhibitor. And in that case, again, it's rather surprising because JAK inhibitors are themselves combinations, right, because that pathway -- that -- those mediators are responsible for multiple cytokine signaling, including IL-23, and they saw an improvement in efficacy when they added Alpha-4-beta-7 on top of a JAK inhibitor. So we feel that, that bodes well for our combinations in IBD.

Maybe generally, I think the idea that an integrin will be combined well with cytokines, I think, is well supported by the evidence as well as just kind of basic mechanistic rationale, which is that the integrin mechanism is blocking immune cell trafficking to the gut specifically, whereas the cytokines are global immune suppressants. And in terms of the benefit risk ratio for an IBD patient where they have an overactive immune system in the gut specifically, kind of getting dual suppression in the gut specifically, but only single suppression globally, I think, is a very compelling approach in terms of blockading this. So it's why I frankly think kind of some of our early readouts here in terms of showing that our Alpha-4-beta-7 is at least as effective as vedolizumab and the long-acting version of it, I do think it is meaningful in terms of making that a great combination component going forward.

And you shared a range of preclinical data across various combination models at conferences over the last year. Are there any key learnings from the preclinical data or data sets that you think are worth highlighting before we get into all these readouts coming up over the next 18 months?

Yes. I mean I'm glad you mentioned that. We've shared publicly preclinical models testing all of our combinations in rodent models. And across the board, the combinations have been better than either of the monotherapies alone. I think -- not just I think we know when we speak to KOLs in this area about what combinations they would prefer, well, I'd say a plurality recommend Alpha-4-beta-7 combined with anti-IL-23. Partly that's just their level of comfort with it -- with those mechanisms. But of course, they're comfortable with them because they're so safe. And so I think that's quite plausible. But from our standpoint, we also see the appeal of potential boost in efficacy with TL1A, as Cameron described, from admittedly cross-trial comparisons. And so we can envision a scenario where a combination of anti-Alpha-4-beta-7 plus anti-TL1A might be really the best in -- especially in UC, where we already know Alpha-4-beta-7 is superior to anti-TNF. And it may be the combination of anti-TL1A and anti-IL-23 is best in Crohn's disease where we know IL-23 MOA is quite effective.

And with the combination readouts expected next year, could you tell us where we might get the first readout next year? And also what expectations for those readouts should be in terms of remission rates as well?

Yes. So in general, the Part B of the study shares comparator groups in terms of the monotherapies and the placebo. So it will be one readout actually. So it will be 6 different active arms against placebo simultaneously. So far, we've just said 2027 in terms of the guidance as we switch from Part A to Part B enrollment shortly and start progressing along those enrollments. I think later in the year, we'll have a better sense of when exactly in '27, we'll get that full readout, but we expect them all -- we know all of them are going to come together. In terms of what we are hoping to see or expecting to see, as we alluded to earlier, I think the main goal here is can any of our combos deliver a set of efficacy that is superior to the other combinations in development maybe a little bit less concerned about the specific deltas between our monotherapies. I think that we likely have the best components, and I think the best components are likely to lead to the best combinations. I think in the long run, what will be compared is the label of a combination product on the market against the other labels of products on the market, not necessarily how much did that combination beat its individual components. I don't think that will be relevant in the long run.

Got it. And you are in a more unique position than any other company, right, with all 3 targets, right, optimized monotherapies against the 3 targets, A4beta7, TL1A and IL-23. And you're going to be able to test all those combos and pick the best one. But you've got the slide showing A4beta7 is better, TL1A is better than TNF. Talk about greater exposure, greater efficacy with both of those targets. Integrin multiplied by cytokines, frontline agent is Alpha-4-beta-7 right, the clear frontline agent of choice. So it feels like you're saying A4beta7, TL1A might be the best combination. I have to ask about that or...

I don't think we know, right? If we knew we wouldn't be running the study, we did. I think what's important about combinations is that the property and the profile of your combo is dictated by the weakest component in the combination and I think what's unique about the Spyre portfolio is that there isn't really a weak link in this portfolio. All of these agents are long-acting. They're engineered for high concentration co-formulations with each other. They were designed for this from the outset. I think when you compare the profiles of our combinations versus the combinations that even the leaders in the field have, we've talked a lot about the J&J combination. But when we look at the other leaders in the field as well, they are not dosing them together on the same interval. They are not the best versions of each of these mechanisms. And I think in some cases, it's hard to envision actually how they become single products that can be delivered as a single injection and priced as a single product as well. I think it is harder to do this than is appreciated. And I think our combinations are likely the 3 best in development. And I think we'll see that in the next 1.5 years as we start to read out the results from the Skyline study.

How do you see the IBD treatment landscape playing out over the long term, right? I guess in some very mild patients, maybe monotherapy is enough to have a tremendous response. But based upon what we anticipate with the combinations, most -- you would think most patients would want to get a well-tolerated combo upfront. And do you go from a combo to a mono or you go from a combo to another combo? And therefore, do you move 2 or all 3 combos into Phase III?

Yes. I think the broad trend in IBD is top-down therapy is the theme, which means patients should get on the best agent first because there are irreversible consequences of having a flare of IBD. You can have surgeries and hospitalizations that you just do not get back to where you were if you let patients get out of remission and so what that's led to is much more rapid advanced therapy uptake, pulling those earlier into the treatment paradigm. And I expect that if you have well-tolerated combinations that provide additive efficacy and you price them so that you can gain relatively early line access, I do think that is where these products are going to be used. In terms of what gets used afterwards, I think it's a very interesting dynamic. I think it's quite unlikely that you will want to use a component of a combination if somebody has failed that combination. I think it is much more like that you will be cycling through different combinations as patients are kind of hopefully staying in remission for longer on combos than they have on monotherapies. But I think it's unlikely that you're going to want to switch to a component of that combination as a monotherapy if you fail the combo. So we think that is likely the way that this field evolves and that it's going to be an efficacy-driven market, and I think that's what we're aiming for here.

All right. Let's move to Skyway, RD and [ Rhum ]. Obviously, Q4 could be a massively value-creating readout for you all, I would argue more so than maybe even the monotherapy data. But can you just briefly state the bar for efficacy there with those readouts that you hope to see? You've got a great slide in the deck, but maybe just voice it over for folks. And do you think there's a higher probability of success in RA, PsA or axSpA? Or do you think they're all quite closely related?

First, can you take the second? So in terms of the -- I mean, we're looking kind of across the target profile, target product profile here, which is convenience first because it's easier because it's well defined, which is that we're testing 2 to 4 shots a year in all of these markets, that would be the best convenience profile on the market. In terms of the safety profile, second, as Josh mentioned, every product, except ORENCIA and RA has a black box warning. So far in 3 maintenance data sets for TL1A, we have not seen safety signals that would justify that as well. So really, kind of the unanswered question that we're interested in here is efficacy, of course, and we'll see those on a placebo-adjusted basis at the end of the year. We think if you're better on convenience, better on safety and comparable on efficacy, that's the winning branded product in this space. So when we show kind of the existing levels of efficacy for the therapies in this space, we think that TL1A has to land in that range to be an attractive commercial product. Of course, I think there's some reasons to believe it could be better than some of the agents out there in terms of the effects on both Th1, Th17 cells as well as fibroblast and fibroblast-like synoviocytes, but I don't think it has to be. I think it could be in the range of efficacy, and it would be just fine. Maybe in terms of probability? I'll let Josh.

I'm not going to give a probability. Obviously, we have reason to believe, as I touched on, across all 3 diseases based on translational data, the genetics and preclinical models in inflammatory arthritis and psoriasis. And if I had to say anything, as Cameron touched on, that might tip the scales. I think that, that is an important concept that we know that TL1A binds to its receptor on fibroblast-like synoviocytes and activates them. And we know that fibroblast-like synoviocytes are really important drivers of both inflammation and joint damage in these diseases. And so I think given that the evidence for the role of FLS is probably strongest in RA, that might tip the scale towards RA. But frankly, we have strong reason to believe in efficacy across all 3 of them.

Yes. And you guys obviously didn't develop the first TL1A. It might be the best, right, or they might be the best based on the properties that we've seen. But how did you guys get in the lead here? And can you talk about the competitive landscape and what you're seeing in terms of others that are perhaps trying to [indiscernible]?

Maybe I'll start here, which is that -- I mean, I think as soon as we started here, we thought that TL1A has a pipeline and the product potential, and we looked at what's the minimum time to get to Phase II proof of concept for each of these things. As soon as we were done in Phase I, we were ready to launch this Phase II trial. Frankly, we were a little bit surprised to be in the lead because we thought the evidence here was very strong. I think it's been nice to see kind of the other strategic in the space follow us into these indications as well. I think without the convenience advantage, they still like the kind of the risk profile of advancing in those Phase II studies. So I think that's been well validating. So how we got there, it's a bit surprising to be in the lead, but I think first-in-class, especially if you're best-in-class is usually a great place to be.

Great.

Yes. I mean I agree. And I think that it's great for us to be leading in first-in-class in the rheumatic diseases. And of course, other companies are looking at some of the other indications. And in that case, we're happy to follow, which we can do if they've established proof of concept in there.

We're up on time here. But in closing, I'll ask you both what aspect of the Spyre story do you believe is most underappreciated by investors right now?

Yes. I think kind of sum of the parts is always difficult for development stage biotechs in terms of -- I think it's pretty easy to get excited about different aspects of our portfolio in terms of I think we have the best combinations in development in IBD. I think these rheumatic disease readouts are very interesting as well. I think it's tricky for people to give credit for everything all at once and recognize what that value is ahead of the readouts. I think as we start to deliver them, I think that value is very likely to accrue. The other challenge, I think, is kind of the appreciation for what these combinations would likely do in IBD. I think we sometimes see folks talking about them as $1 billion, $2 billion, $3 billion a year drugs. I don't think that's actually likely in terms of the dominant products in IBD don't do low single-digit billions. They do high single-digit billions. And I think we have the 3 best ones in development. They may not all turn out to be 1, 2 and 3 in the end, but even 1 or 2 of them in that range would be a major value inflection from where we're trading today.

Indeed. Wonderful. Thank you so much for your time, Kim and Josh. Appreciate it.

Thank you.

Thanks, everyone, for joining.