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

All right. Good morning, everyone. Really appreciate you joining us. My name is Akash Tewari. I am a pharma and biotech analyst here at Jefferies. And this is day 1 of our wonderful New York Healthcare Conference. I've got Cameron from Spyre. Cameron, why don't I give it -- hand it off to you for some brief introductory remarks, and then we'll get started with the Q&A.

Sounds good. Thanks for having me, as always. So the brief background on Spyre is that we launched the company about 2 years ago with a pretty straightforward goal, which was to develop a set of products that we believe could address the unmet need in inflammatory bowel disease, which we really saw as two things. One, the efficacy in inflammatory bowel disease is still dramatically lacking relative to other large I&I categories, with most approved products delivering a placebo-adjusted clinical remission rate rarely above 25%. And that leads to patients and physicians having to cycle through many medications to get to lasting remission, which, in many cases, they never achieve. And then second, despite this being a disease that affects more than 2 million people in the U.S. and many more in the rest of the world, we still have, I would say, relatively inconvenient product profiles on the market today as well. So things that are dosed as frequently as every week or 2 weeks subcutaneously or having patients to still come in and get intravenous therapies quite regularly. And we thought we could address both of these things with our portfolio. And really, that's in two ways. One, we're going to develop longer-acting versions of what we think are the best biologics in this space, alpha 4 beta 7, TL1A and IL-23, which we think can meaningfully extend the dosing interval and get to quarterly, if not twice, annual subcutaneous dosing, which is a much better profile than what's on the market today. And then we can both adjust the dosing of these products as well as dose them together in combinations, which we think the two of those things together has the potential to dramatically improve the efficacy compared to today's standard of care. And so we're developing these together in what we think is a pretty ambitious and exciting Phase II study that's starting imminently.

Love it. All right. So let's get started. And we've had this discussion before. In terms of our own fundamental diligence, bispecifics versus co-formulations, higher ADAs, I don't necessarily see a benefit, especially when you have different half-lives or different levels of target engagement. Some of these are soluble targets, some of these are not. So I don't see a clear advantage of a bispecific over a well-run co-form. That's why we like Spyre. The one fair critique that I think investors bring, and I think you've seen some of the strategics think about this, too, contribution of care and how do you get to novel, novel combos and the FDA comfortable with that in a very quick competitive environment. Talk to me about how Spyre is thinking about those challenges, particularly in terms of your Phase II design that's coming out.

Yes. So I start actually with where you started as well, which is if we look forward kind of a few years to the end of these development programs, which approach for developing combination therapies is likely to lead to the superior product profile? And I think you have to start there because this is a -- it's a long-term game in terms of having how long these products are on the market. And when we, at the outset here, looked at the opportunity to look at a bispecific versus a co-formulation, and we thought there's really no argument that the bispecific will be better than a co-formulation and quite a few reasons why it could be inferior to a co-formulation. And you highlighted them as well. I think it's most importantly, the ability to have the right amount of target engagement for each of them versus being fixed in a 1:1 ratio and not necessarily getting the same in vivo activity that sometimes see in vitro for bispecifics. And then second, the immunogenicity risk that you highlighted. I particularly like to look back at the history of the TNF bispecifics, where this isn't the first time people tried to make multi-specific antibodies. There were a dozen TNF bispecifics that were made, and they all got discontinued after Phase I or Phase II for one of these two reasons that I just described. So we think if you look forward, the long-term winner here is likely to be co-formulated antibodies. To get there, as you highlighted there, you do have to go through more to get there, which I'm not sure makes sense scientifically, but that's the reality that we have to show that our combination shows contribution of components that our combinations, be it our monotherapies and our monotherapies, be it our placebo; that's what our Phase II is designed to test. So it's a platform study that includes a placebo arm. It includes our 3 monotherapies, and it includes the 3 paralyzed combinations thereof. We think the study is adequately designed and powered to test that, that our combos can be our monos, our monos be placebo and then hopefully have the ability to move forward whatever the winner is from that study to a pivotal program.

Got it. Now as we think about that Phase II, and I think people think, okay, there's one combo that's going to get tested in these Phase II studies, there is kind of the optionality that you could have multiple combinations added into that Phase II. This could end up being kind of a larger program. And I don't think that's necessarily well appreciated with the Street. So can you talk about the flexibility you anticipate in that Phase II design if you want to try the ENTYVIO or if you want to try the IL-23 in combination with, let's say, TL1A? What's going on there?

Yes. So the study is designed as a platform study, meaning it is a one master protocol that includes the same site, same investigators, same inclusion/exclusion criteria for these arms. And then we'll be activating sites actually starting now basically over the next year or so to start enrolling patients across all of these different arms. And the study is designed to test our entire portfolio in a single platform study. So the 3 monotherapies and the 3 pairwise comparisons. I think we and most of the experts in this field don't yet know which combos are likely to be best, and we think this is the best way to evaluate them, is to test them head-to-head and see in the same population, which one is superior so that we can pick the winner to move forward. I say winner a little bit flippantly in that I think it is possible that there's more than one winner coming out of this trial. I will talk about the rationale for each of these, I'm sure. But in general, we think these are the 3 best biologic targets in this space. We have compelling evidence from human genetics, from animal studies or even just the basic biology of these targets that there's likely additive efficacy to be had between each of our 3 targets. And we think for the most part, these are the safest targets in IBD as well, particularly alpha 4 beta 7, but then IL-23. TL1A, we know the least about its safety. But so far, it looks very clean as well.

Actually, I want to hit on that because I remember you and I talked about this, and you said you're like, look, TL1A is a TNF superfamily. We don't have long enough durability data. So you said it's notable that we're thinking about the alpha4, beta7, IL-23 combo and not necessarily the TL1A in combination yet. That was a year ago. Now we do have across the board, whether it's Teva, whether it's Merck, whether it's Roche, we have durability data. We're not necessarily seeing a severe infection signal show up with the TL1A class. How does that change your priorities in terms of exploring TL1A in a combination setting now?

Yes. I think -- I mean we've always been excited about TL1A as a class, and I think that the longer-term data continues to support that it probably has the best efficacy of any individual biologic class in IBD, and we haven't yet seen, to your point, the safety downsides that we've seen with other classes like the TNF or like the JAK class certainly. That said, it's still nowhere close to the amount of exposure that we have for vedolizumab or for the IL-23 classes, where you have tens of thousands of patients dosed across the clinical studies there and in the commercial setting. So I think the relative order of certainty is still the same, though I'm increasingly feeling confident that the TL1A class has a nice safety profile as well as we see greater and greater exposure with that class.

That class. Okay. Understood. Now in terms of how do you see the TL1A class play out because I think Teva has a very potent drug, I don't think Teva has a very great half-life. I think you look at the original Roivant compound, issues in terms of getting this into a subcu and then potentially ADAs. And then Prometheus looks like a viable compound, but maybe there was some potency left on the table. When you think about you have 2 TL1As that you have, how do you think, given it's a very competitive space and there's already billions of dollars invested ahead of you that you can have a compound that would differentiate here?

Yes. I mean I think you highlighted where we started, which was we didn't think any of the first-generation TL1As had the set of properties that would be an ultimately best-in-class molecule in -- against a target that I think we and everyone who spent the amount that they have to buy those assets and develop them believes this is probably not just a single indication target. There are many potential indications to go after. And the evidence in at least in IBD now is that it's not just like TNF, it's maybe better than TNF in that indication at least, and we might see that play out in adjacent indications as well. So -- but when we looked at this, we saw none of the TL1As that had developed had that optimal set of properties. None, of course, incorporated the half-life extending approach that we've taken across all of ours. But then you highlighted the 3 weaknesses that we saw as well, the low potency for the Prometheus molecule, the immunogenicity formulation and bioavailability issues with the Roche molecule and then the short half-life with the Teva molecule. And really, we thought, look, we can go make a better version than any of those. And I think in the next few weeks here, we'll report data from our 2 Phase I studies on these molecules that I think should do a pretty good job of demonstrating whether we've achieved that of really ticking all those boxes of a highly potent, long-acting full target engagement and low immunogenicity molecule. If we have at least one of those, I think we would be very excited not just to add it to our IBD Phase II study, but as we've announced, we're interested in testing TL1A in rheumatology as well.

So I want to hit on -- okay, so I understand the comments. Let's think about your competitors and make some hot takes. Teva, okay. So you have a very good response rate. They dose the drug quite frequently every 2 weeks. You're now going into maintenance, and you've got 2 populations. You've got UC and you've got Crohn's. So I want you to call your shot a bit. When you think of it -- because we're figuring this out too. As you think about going into monthly dosing with the Teva molecule, how do you expect efficacy to drop? Because there is another side, which says, look, once you've done the induction, you don't need to press on the lever as potently and you might not see efficacy drop that much. So what gives you -- what's your view on how that Teva data set evolves?

Yes. So I think I will refer to the other 2 TL1A data sets because I think they're quite informative for how the Teva one is likely to play out. So I think in general, we've seen now 3 induction TL1A data sets that the properties of the molecules are all different and the dosing has been dramatically different from -- as low as 50 milligrams from -- in the Pfizer study initially to the Teva molecule over the induction setting is dosing more than 5 grams. So really a very wide range of dosing there. And I think it's fair to say that at the high end, the placebo-adjusted clinical remission for those molecules doesn't look that different. The enrollment populations look quite different. The placebo rate varied quite a bit between those 3 studies, but the placebo-adjusted efficacy looked quite similar. That's -- and I don't think we saw a meaningful dose response for any except Teva, right, in the induction setting. In the maintenance setting, I think the story might be a little bit different in that both of the first 2 molecules that have reported maintenance data, both Roche and the Merck molecule now, they show dose responses. Not on every endpoint in the study, but I think on the most objective endoscopic endpoints, we saw a dose response in the maintenance setting. And when you see that your highest dose tested was your most efficacious dose, you never know if you actually hit it completely, if you're already at the plateau of efficacy or if you might have missed it. And I think we actually see that Merck probably believed that as well because when they went to their Phase III study in Crohn's, they actually dropped the dosing interval from every 4 weeks to every 2 weeks. So it looks like they believe they might have missed the maximal efficacy in the maintenance setting as well. So -- and now we're kind of read through to Teva. As you mentioned, they have the shortest half-life of the 3. The other 2 have about a 19-day half-life, and the Teva molecules half-life is less than 10 days, and they're all dosing monthly. So there's a big difference in a half-life when you double the dosing interval. It's not a linear effect. It's -- you lose a full half-life or 2 there. And I think they will have a harder time covering the target in the maintenance setting. I don't think that will be the case for ours. We'll see our half-life here in the next few weeks of our molecules. But if we have the potency and the half-life that we would expect based on our NHP studies, then you -- I think we have a pretty good probability of being able to fully cover the target, not just in induction, but in the maintenance setting as well. Even if we extend the dosing interval out to quarterly, again, that half-life translates quite well as you get to those long dosing intervals.

Understood. Now let's talk a bit about -- and again, it's funny, as much as you're generating data, it's what's going on in the space broadly that I think is also equally relevant. You've got to DUET studies. And actually, look, you have multiple approaches with that kind of TNF combo studies that J&J is running. Talk to me about what expectations are because this is -- I think the #1 thing I worry about is you look at some of the early studies, and this is what J&J talks about, too; it looks like 1 plus 1 equals 2. That's in a biologically naive population. I think there's a lot of differences between naive and experienced patients, especially if you look at some of the methotrexate or TNF studies historically. So a, can you talk about some of the data sets you're watching from J&J over the next year and the read across you think they're going to have to the combo approaches you're taking into the clinic? Yes.

So I think -- so J&J is running 3 studies now that I think we're paying attention to. The 2 that are most relevant, of course, are the 2 DUET studies in Crohn's and UC. I think those studies have completed now. I think I would expect they know the data in the upcoming weeks, if not the next couple of months. When we see it publicly, that's a little bit less certain right now, but I think we will see those data in the upcoming quarters here. And then beyond the DUET studies, I think we're also interested in the same combination in psoriatic arthritis. They're running a study called the AFFINITY study, which is looking at all TNF refractory patients and then they're either getting IL-23 or the TNF and IL-23 together. And I think the combination of those 3 studies, I think, will help us answer a lot of questions really about the future of combination therapy, mostly in IBD, but then also kind of expanding to other hard-to-treat I&I diseases. And I think the main questions that we're trying to answer, so far, we have a clear answer for how well the combinations perform in naive ulcerative colitis patients. I think in the DUET studies, we're going to see how the combinations perform in refractory UC and Crohn's patients. And then I think what we're really most interested in is, okay, what's going to come next from this study? Are they going to go to a Phase III study? I think for now, a reasonable assumption is that will be a mixed population, a mix of naive and refractory patients as most drugs have been approved in IBD. And so I think what we're interested in is what do we expect the overall profile to look like for that J&J combo in a truly mixed population of about a 50-50 naive biorefractory population, that mix of the VEGA result in the naive population and then what we'll see in DUET in the refractory population.

Okay. And so now let's talk about expectation setting because I think that's important. I think historically, and by historically, I mean just last year; people think, okay, if a combo can show a 10% delta over a monotherapy, great. There's evidence of additive benefit. I think that's a -- we need to delineate that between in a naive setting and in a refractory setting and also into some of those indications that J&J is pursuing here because it also seems like body language is different, depending on what -- like maybe psoriatic arthritis is a little more bullish than, let's say, Crohn's. So how would you set the bar? If you're going to say, as an investor and you're looking at this data set, what would be a delta in a refractory population in some of these disease states that would say to you, "Hey, I am seeing combination activity that justifies the risk-benefit profile here"?

Yes. So I look at kind of two data points that help us guide what the benchmark should be. One is our work with prescribing physicians in this space. So we kind of just do surveys here to see what a meaningful difference would be that would lead to a change in prescribing patterns. And then second, looking at precedents in this space as well. There have been plenty of head-to-head studies. There's a handful of head-to-head studies run in this space that have led to changes in practice with differing levels of clinical remission deltas. And I think between the two of those, I think it lines up reasonably well that once you get to a double-digit difference overall in the overall population, that mixed population, if you have a double-digit difference, we see a meaningful shift in prescribing preferences. I think that's comparable to what we see in the head-to-head studies of the IL-23 p19 inhibitors compared to the p40 inhibitors that have led to a substantial practice shift. And that's more than what was seen in the VARSITY study comparing alpha 4 beta 7 compared to TNF, which also led to a meaningful practice shift. So I think we know that even in that kind of high single-digit to low double-digit percentage range, that's where you see physicians change their prescribing patterns and believe that something is clinically meaningfully different. So now to back out to your original question, we think that's what you need overall. I think kind of if you're in that double-digit percentage overall in a mixed naive and refractory population, that would lead to a meaningful practice shift. We know in the VEGA study, it was more than a 20 percentage point difference between the monotherapies and the combos. I think we want to see something in the refractory population, too, but it could actually be slightly below 10%. And I think you would still have a high probability of seeing a more than double-digit percentage in a Phase III study where you mix those populations together. So that's really what we're looking for is, okay, if we read through to what Phase III are they going to run, what's the delta they're going to see? And therefore, are they going to be able to move many patients.

So 5% to 10%, you might see that...

5% to 10% in refractory, and it's where it was in the naive population. I think that's a dominant product. I think it's worth remembering, they haven't seen any downside in safety yet. I think that will be critical. This is a TNF combo. We're seeing it for the first time in maintenance now. So safety will be critical. And then I also expect, which I think takes some education of the various stakeholders here, that I expect J&J like ours, I think it's more likely that these are priced like one product. This is one branded product. It's not going to be adding two branded things together. And so I think you're really comparing against the same properties as normal, efficacy, safety and access. And I think in this case, the efficacy is likely to be better. The safety hasn't been worse. And if you price it the same, I think that's a dominant product.

Tell that to AbbVie, given where Rinvoq is priced versus Humira, but I digress. Okay. Now let me -- I'll give you the tough question. Let's say that, that refractory delta is 0% to 5% in, let's say, Crohn's. Does Spyre as an organization look at that study and say, "We are still going to pursue combination in Crohn's"? Or do they say, "You know what, we have limited capital. We want to be smart about where we're exploring these studies. We're not going to go forward in that indication"?

Yes. I think, in general, I think first, I think there's many reasons that our combos are likely to outperform the J&J combo kind of regardless. And I think we can talk to this specifically, but I think alpha 4 beta 7 beats TNF head-to-head in this population. TL1A has been tested head-to-head against TNF, but I think most would agree that TL1A is superior to TNF as well. So I think regardless of what J&J shows in the DUET studies, I think our combos are likely to outperform them. That said, we're obviously going to learn from DUET. I mean this is, as I mentioned, kind of 2 new populations that we're seeing this combo activity in. We can certainly adjust our development plan, depending if they see a meaningfully different delta in those populations versus what they saw in VEGA. So whether we need to do a kind of a normal 50-50 mix where we want to adjust our population, how we decide to approach Crohn's, we've only announced our ulcerative colitis trial, but we are interested in pursuing Crohn's in the long run here, of course, too. But we'll learn quite a bit from these DUET studies. And of course, we'll incorporate that into our strategy here.

Makes sense. Now just on TL1A, there are two angles here, right? There's the I&I indications that I think we all are familiar with from our large-cap companies, but then you have signals in liver diseases, systemic sclerosis, et cetera, et cetera. And you have multiple TL1As. Can you talk about TL1A in a more orphan setting? What does that regulatory path look like? And where are you from a competitive perspective versus some of your peers? I think Merck is exploring some of those indications as well.

Yes. So I think beyond IBD, where we have, of course, seen 3 successful ulcerative colitis trials and 1 successful -- I guess, 2 successful Crohn's studies, where we've Merck or Prometheus at the time had launched an SSc-ILD study that I expect will read out next year as well in Merck's hands. And then over the last few months, we've seen a flurry of additional trials get announced or launched, one in atopic dermatitis, one in HS and one in [ NASH ], as you highlighted. And then we announced that we'll be testing ours in rheumatoid arthritis as well. So I think it's -- everyone is interested in a range of different applications here. This is a TNF superfamily protein, but it also hits, I think, most interestingly, an antifibrotic angle as well. And so we and others are interested in indications that have reasonable derisking on the inflammatory side, but may also have an antifibrotic component that we think could be valuable, too. And you'll see kind of in these different indication selections, a different prioritization of that antifibrotic kind of newer angle versus kind of continuing to go after inflammation, where I think you have kind of more derisking now, given the positive results in both UC and Crohn's.

Got it. Maybe just I want to touch a bit on the strategic stuff. So you have two different developments. I mean, if anything, you have multiple huge indications that take huge sales forces. And then you also have an angle where you're trying TL1A in indications that haven't occurred before. We'll save the larger partnership and strategic question. But let's just say about these more orphan niche indications, which still could be quite big, especially if you think about different price points. Why not partner out some of those now, get more cash on the balance sheet, give you more strategic optionality rather than take them forward yourself? And is that a decision we might get relatively quickly?

Yes, that was not lost on us when we decided to take two molecules forward. The original idea was that, "Hey, there's not everything you can derisk preclinically before you go into Phase I and really just wanted to have the maximum chance that we have a great TL1A molecule coming out of it." The reality is we could have two great TL1As coming out of it. And I think the value maximizing strategy for us is probably to use them both, whether ourselves or through a partner. If you only have one, that option doesn't really exist because most larger companies wouldn't be interested in splitting indications with you for one molecule. But if we have two excellent molecules, that is an option that we have on the table. I think in general, we're very well financed at this point. We still have $565 million on the balance sheet. We're still fully funded for the full platform study in UC plus our RA study. So we're in no urgency to raise additional money. But I think particularly on the other side of Phase II, I think there's a lot of potential Phase IIIs that could come out of this portfolio. And I think we will have to be quite savvy about how we decide what things we're doing ourselves versus what things we may decide to partner on.

So you answered for some of those other indications. I'll ask also for the big enchilada in terms of UC, Crohn's, atopic dermatitis. It seems like to me, when you think about a platform study and you've designed it this way, there is a speed advantage in terms of generating multiple combinations that I think you would have over a lot of your peers, even the bispecifics are a little behind you right now. How important is getting that card flip both for Spyre as a company, but maybe for strategics? What do you think is derisked once you have all that data available to you?

I mean I think it's critical. And I would look at the precedents in this space that you can enroll a study that's 200 patients across 100 sites in 1.5 years or 2 years. But look at the DUET studies. Those studies enrolled 600 patients and not that different a time frame because they went out much broader to more sites, they had a lower placebo allocation and then they have a high proportion of combinations enrolling in that study. And despite only enrolling refractory patients, those studies enrolled incredibly well. They enrolled in about a little over 1.5 years for these huge studies. And so I think that kind of shows you the power of running larger studies with multiple active intervention arms that I think we'll likely see a similar advantage here. Of course, we have very low placebo allocation in our study, a high proportion of combinations. And in fact, all of our combinations are be dosed on a quarterly basis, which will also make it the most convenient study to participate in as well. And I think -- so this -- we only have to activate sites once in this study. The total number of patients we need is kind of on the order of we say, 40% relative to running these as separate combo studies. I think it's massively efficient. And in a challenging biotech capital market, we're trying to be as thoughtful as we can about what's the most efficient way to generate answers that are the most valuable. And in our view, that's how do we get to those 3 combination readouts with the cash we have. And this is really the only answer. And I also think it's an answer that no one else can really do without the portfolio that we have.

Makes sense. Now I want to hit on ENTYVIO. We were talking about [ forLer ], where is the [ morphic ] data, where is, I guess, the [ Lilly ] data now. And it's interesting. A lot of people don't talk about, I think, the alpha4, beta7. But there is -- one of the things we're thinking about is if there is an early critique on TL1A, obviously, the end is low, what is the efficacy in TNF refractory patients, right? And I think that's a fair discussion point to have. And -- at the same time, ENTYVIO is one of those targets, which actually does perform particularly well in that population. So when you think about combination approaches with your ENTYVIO, a, do you think there's going to be an efficacy advantage because you're having higher potency? But then b, why should we be thinking about maybe the ENTYVIO target as the optimal combo partner when you're thinking about an IL-23 or TL1A versus maybe other approaches that you might have in the bench?

Yes. I mean when we start -- there's a reason alpha4 beta7 is our first program. And that is, a, is the #1 product in IBD. So that's a good place to start. And the most obvious reason is the safety of it. And the safety that's an unsurprisingly excellent safety because it's a gut-selective mechanism. So you don't expect to see those broader infection and malignancy risk that you see with other classes and you don't. It doesn't have that risk in the label. And so we think it's the excellent molecule to start with, plus the biology is very orthogonal to the other targets that we're going after. It's a cell trafficking mechanism relative to the anti-cytokines that we're going after with TL1A and IL-23. So we think alpha 4 is a very logical target to go after. I still think there is potentially a synergistic approach between TL1A and IL-23 and whereas I view alpha 4 beta 7 as a more orthogonal biology than hitting those cytokines. But as I mentioned previously, we see additive, if not synergistic, efficacy across a range of in vitro and animal models for our combinations. And because we have long-acting versions of each of these, we think we have quarterly plus combinations, where kind of the safety of each of these targets looks good individually and the efficacy looks good individually. I think they're most likely to be the best combos in the space.

Understood. Now -- but let's just hit on with the ENTYVIO induction. And let's put it this way. Do you believe there is a dose response that ENTYVIO shows across different ranges? Because again, I struggle with understanding receptor occupancy and its correlation on efficacy and maybe just the general MOA here. So when you have a much more potent drug like you have where you're probably in the highest [ quartile ] of induction, do you expect there to be an efficacy advantage angle that Spyre is going to pursue beyond just dosing?

Yes. We see that -- we tend to position that as the upside case. But I think the data is reasonably strong here that both in the pivotal studies and in the real-world setting, we see that the more vedolizumab you have on board in the induction setting, the higher probability of clinical remission. Now that was something that the FDA highlighted to Takeda at the BLA time to say, "Hey, you should go test a higher dose" because we're developing this from scratch, we have that opportunity to go test a higher dose. And as you mentioned, we plan to put kind of all patients in our Phase II study into that fourth quartile of exposure where vedolizumab had much greater clinical remission rate. Now I think that's not likely to be doubling the efficacy of vedolizumab, but I would be surprised if we're not able to improve the efficacy by having that greater coverage. But we'll see. We'll test that in the Phase II study and see if we deliver higher remission rates.

Got it. And I'll talk more generally here because, obviously, we're a ways away from the pivotal combo studies at this point. But from what you've seen across your profiles, what you've seen with your competitors, generally speaking, the investor bar is that in a refractory population, if a combination can show a 5% to 10% benefit that would be clinically meaningful. Are you comfortable with that bar with the Spyre combinations that you think you're going to be taking forward into the clinic? Or is it higher?

I mean I think if you didn't show a 5% to 10% benefit of your combinations over your monos, you wouldn't show contribution of components either. I think that's what you need to see to be clinically meaningfully better. And I think that's what we're aiming for. We're aiming for a clinically meaningful improvement in efficacy without a downside in safety and do it all on a quarterly plus basis.

And then maybe to that point, on a Phase II study or a Phase III study, is there appetite on Spyre to run superiority studies versus some of the existing standard of care?

I would be -- I think it's very likely that we will. I mean we know 2 of our 3 monotherapies would beat the biosimilars today. Our alpha 4 beats TNF head-to-head. Our IL-23 would likely beat the p40 head-to-head. So the 2 biosimilars in this class, we already know that our monotherapies would beat them. If our combos beat our monos in Phase II, I think there's basically any product on the market, our combos would likely to beat head-to-head.

Understood. And then if I could sneak in one more. In terms of the bispecifics, and again, call your shot here, there are a lot in China that large-cap pharmas actually move forward with differences in terms of inhibition, difference in terms of receptor turnover. Do you think the bispecifics are going to be able to be potent enough and dosed enough to have a quarterly profile and potentially a higher exposure advantage?

No.

Okay. We're out of time. Thank you so much for everyone for joining us. Cameron, always enjoy our conversations. Thank you, guys. All right.