For those who don't know me, my name's Akash Tewari. I'm a Pharma and Biotech Analyst here at Jefferies. This is the Jefferies Healthcare Conference in beautifu l Times Square. I have the pleasure of hosting the Spyre management team. Cameron, it's so great to have you join. A year ago, you were maybe a figment in Peter Harwin's mind, who knows? But I hand it off to you for some brief intro remarks, and then we'll get going. Yeah. Thanks, Akash. So yeah, as you just mentioned, we're almost exactly a year from when we launched Spyre. And I think we've made a ton of progress over the last year. As you know, we have three programs that we're pushing forward in parallel, α4β7, TL1A, and IL-23. I think we're excited to be imminently becoming a clinical company here in the next couple of weeks. So we'll be dosing with our α4β7 program by the end of the month, and actually just got regulatory clearance on that in the last couple days. So we should be in good shape to start dosing and have data on that first program by the end of the year. Okay. That's, that's awesome. So, I wanted to start off. I know there's a lot of focus on the combination approach, but let's, let's actually talk about TL1A. And, you know, again, a year ago, we saw Large-C ap Pharma do two major deals in that space, in some instances, on phase II data. This is very unusual. But not all these molecules are actually created the same, and I think there's not great appreciation for that, even for some of the you know, players who have come from behind, like Teva and Sanofi. So can you talk to us about how you see the landscape and then your drug, where does it kind of fit when it comes to the exposure levels on TL1A that you're able to have, but more importantly, dosing and how you dose, where I think people might see some differentiation that's not appreciated right now? Yeah, so I think the place to start is like, why did we even make this set of molecules? And really, this was before I joined here, but really looking at the phase I data sets at the time from just Pfizer and Prometheus, and really saw kind of two very distinct antibodies in terms of their properties. On one hand, you had a Prometheus antibody that has binds kind of both the monomeric and trimeric form of TL1A, and it has good bioavailability, a relatively low ADA rate as well for that molecule, but its potency was lower than you might expect- Mm. F or a kind of industry-grade antibody. And then on the Pfizer side, kind of the opposite. They had pretty, pretty good potency, the bioavailability maybe less than you might hope for, and then the ADA rate that was, probably higher than you would expect as well. And that really was the driver of, "I think we can probably make an antibody that puts all of those properties together in a single product," and then neither of those had any half-life extension either, and- Right. S o far, it looked like a target that does not seem to have an acute safety signal, and so half-life extension makes a lot of sense for that target as well. So that really is the, the target profile that we went after, and I think we've thus far showed pre-clinically that we have a molecules that have great potency, that have selectivity as well for this target, and then have a half-life that is more than double the non-human primates compared to those existing antibodies, and we think should enable, probably quarterly plus dosing on that target. Understood. And I actually wanted to hit on two, both Merck and then also Teva and Sanofi. I think we saw with Teva and Sanofi, I think, earlier this year or late last year, the time is becoming hazy, but that the half-life of that molecule might be shorter than I think investors understand. If you go on their EMA filings, they're actually going for two-week dosing in some of these instances. But then there's also Merck and kind of their half-life. Can you talk to us- Yeah, of course. ... about what you've seen in the competitive landscape? Yeah, so the half-life of the molecules, as far as we can see with the clinical data, is that the Pfizer and Prometheus antibody have quite similar half-lives, just under 20 days, and we've got about 19 days for each of those molecules. Whereas the Teva Sanofi molecule is in the 7-9-day range, which they showed earlier this year at ECCO. And then the dosing intervals for those molecules is a bit counterintuitive, given what I just said about half-lives, where the Prometheus molecule is being dosed monthly. Though we just saw from Merck that in their Crohn's study, they're actually including a 2-week dosing interval on the molecule that Prometheus developed. And then in the Teva Sanofi case, they have a much shorter half-life molecule. They're dosing up in terms of much higher dose of the molecule and then trying to use that higher dose to get longer-term coverage despite their shorter half-life. Understood. Now, when it comes to TL1A, you know, I think there's still a lot that we don't know, right? There could be safety issues with this molecule that show up longer term as well. You know, we need the data. But when you think about a compound like yours, where you could have theoretically lower effective exposure, but then longer half-life, where do you think you could fit from a therapeutic window perspective that maybe some of your peers wouldn't? 'Cause it does seem clear that occupancy is important. Yep. So where do you guys kind of position yourselves versus Sanofi, Teva, and Merck? Yeah. So I think, I mean, potency, of course, you can always adjust your dose to get to a saturation on a target. And so from a therapeutic window perspective, how we think about it is the improvement in potency allows you to get to saturation on the target with a much lower amount of drug on board. And we've frankly seen that really with the Pfizer, now Roche program, that they can have hundreds of milligrams of dosing to get to saturation, whereas the Prometheus, now Merck molecule, doses up to a gram or so of drug to get to saturation because their potency is lower. So from a safety efficacy perspective, the advantage of high potency and lower drug load is that your risk for off-target effects when you have just lower amount of drug on board is lower. And so the potential that you'll have off-target safety issues is a lot lower if you have a more potent molecule on the target specifically. So that really is the advantage, that we think we shouldn't have to dose 1 g, 2 g of drug- Mm ... to get to saturation. We also shouldn't have to dose very frequently because our half-life is more than double the longer of the two, longer of the three molecules that are ahead of us as well. Understood. Now, you know, I cover Merck. I... It's been hard to get information from Merck after the Prometheus acquisition about really where TL1A is positioned. You don't spend, you know, $11 billion on a phase II asset when you don't think that this is gonna be kind of paradigm changing. But I think the question for investors is, are we going first line with a biomarker approach where, hey, we can stratify patients and maybe get responses we couldn't see without it? Or we're actually really efficacious without that stratification, and it may not make sense commercially to actually implement that. If you were, you know, Merck right now, and you were gonna make a decision, would you be going for the biomarker agnostic approach, or would you go- be going for that biomarker approach in first line? I mean, I think what we've seen with their trial design is they're—so, how you would use a selection approach, there are kind of levels of how much you believe in it, really. Sure. ... in terms of how you use it in the trial, and their trial designs suggest not extremely high in terms of they're not enriching for a population with a particular genetic background. They're not using certainly it as a true companion diagnostic that you need that genetic background to enroll in the study. It is a, it is a subgroup analysis that they're doing. Whether or not that makes it into the label and into commercial practice, I think will depend on the size of that subgroup and the, the level of effect that they see there, but it's certainly not a, "Hey, we're all in on this biomarker-based strategy in terms of selecting that." So I, I think that that's kind of voting with their feet in terms of trial design overall here. Hmm. I think that's it—so it does beg the question that you said, are you actually going for that CDx positive group in the commercial setting? It looks like less that way, that it's more of an all-comer strategy, in which case, the all-comer data for TL1A, as you know, is very good. Right. But is it how differentiated is it from the other first-line monotherapy agents? I think that that'll be the commercial question there. So then there's a question for you. Mm-hmm. If that's what Merck would do, knowing, let's say, that Merck does go without the biomarker approach- Yeah Y ou know, I think you've seen data, particularly in Crohn's disease, right? I think there is data in Europe where using Remicade first line, the incidence of patients actually needing surgery was 10x lower. I think in, especially in something like Crohn's, hitting the therapy aggressively upfront may make a difference here. Do you feel like there might be an opening for a biomarker-driven approach in first line with Crohn's with your molecule, where you might be able to show best-in-class efficacy and really make that argument you should be used over things like methotrexate, but also some of the biologics that are going off patent? Yeah, so, so I think... I mean, I guess my view of the future here is that the, the first-line therapy, to get used there, you need to show a meaningful efficacy advantage, right? And so I think there's really two ways that we're pursuing that, or maybe three ways, but two that I would, I would put, a heavier bet on, which is.. Hmm T he one that I think is the most likely, in terms of the monotherapy differences in efficacy have been, I would say, I think modest is fair to say. If you look at TL1A- Right. A nd all comers, it's closer to the other monotherapies than it is to what I would say is the only thing that has definitively broken the efficacy ceiling in this space, which is VEGA. I think that is the only study that I can look at and say, "That is definitively superior to the other monotherapies. That was double the efficacy, functionally additive efficacy in that study." We have to wait to see if that plays out in DUET and moving forward. But if I think kind of what's competitive first line, when you double the efficacy, that's the answer. I think from a biomarker-driven strategy perspective, we saw the deltas that were observed with both Prometheus and the Teva approach for selecting patients. That was not a doubling of efficacy, and at the same time, it narrows your patient population as well. Right. So I think, I think it's an incremental advantage. We are developing selection strategies for our programs as well. I think we see opportunities that are of a next-generation approach to patient selection versus the approaches that we've seen for the existing agents. But I think that's likely to be a more modest effect on the efficacy than, I think, leaning into hitting- Mm-hmm ... kind of two well-tolerated targets simultaneously. Understood. And you mentioned VEGA, and I think this is really important because one of the things I think that gets me a little nervous is investors have been taught to look at VEGA or SONIC, and a lot of these studies were 1 + 1 = 2 when you're combining I&I targets. But there's also a lot of data when we get into an ex-biologic experienced patient, particularly in combinations with methotrexate, where we don't necessarily see that additive effect. So with that premise in mind, let's talk about DUET. This is a, you know, the, the J&J studies that are coming out, it's, you know, the TNF in combination. I think it's the IL-23. p19, yeah. p19, yeah. How do those results impact what Spyre's clinical development path is going to be with your combination approach? And talk to me both from a safety perspective, but also in an efficacy perspective. Yeah. So I think just to level set, so VEGA was, as we've just mentioned, the TNF plus the p19. They co-administered those two antibodies, but they only co-administered them during the induction period. They then dropped the TNF. So what I think the unanswered questions, and it was all in a naive population- Right As you just mentioned as well. So those, I think, beget the two, the obvious questions, which is, what happens in a refractory population, and what happens with that combination in long-term development as well? DUET will answer both of those questions because DUET is a co-administration, or sorry, a co-formulation of the two antibodies, so it's dosed throughout. And then it's also a refractory patient population- Right A ll exposed to prior biologics. So I think the main questions functionally are, okay, you have a TNF plus an additional immunosuppressive agent. Do you have TNF-like safety, or do you have something that's different than that? From our perspective, I think the combinations that we're looking at, we think they all could be superior because we don't include a TNF. In particular, α4β7 has superior safety and efficacy in a head-to-head VARSITY study, where α4β7 beat TNF individually, and IL-23 we know is a very well-tolerated target overall. Right. So you functionally have VEGA or DUET swapping out a TNF for an α4β7. We also have that combination swapping out a TNF for a TL1A, which has also shown both superior safety and efficacy, not in a head-to-head study, but I think at this point it, it looks superior, though it's earlier. Understood. Now, I think you're hitting on something that's kind of important here. When I talk to you, it doesn't seem like TL1A is the first thing you bring up when you're thinking about combination approaches. And I think a lot of people ignore the Entyvio and the IL-23 'cause TL1A is kind of the shiny object. Yeah. But when you think about, if you were to ask yourself, like, hey, if you're gonna pick a combo approach, and Spyre, in many ways, is becoming this combination story, why would maybe the IL-23, you know, Entyvio combo be preferable in a combination setting versus TL1A? Yeah, so when we talk to our scientific advisory board, which is, I think, the same as everyone else's scientific advisory board in this space- Yeah K ind of the top KOLs here, when they look at the three combinations we have, the α4 IL-23 is the one that from a comfort that the safety is going to look good, that's the one that they have the highest certainty around. Because we have tens of thousands of patients experience α4β7 and IL-23 in large controlled studies, and these are very well-tolerated individual agents. The biology is orthogonal. Right. You're not hitting the same pathways in the same ways, and I think from a safety perspective, which, I mean, frankly, that's why vedolizumab is used as much as it is. It's an extraordinarily safe molecule. And so that is really the why we wanna start with that combination of α4β7 and IL-23 as something that we think is high probability. TL1A, as you said, shiny new object, really great-looking monotherapy data as well. I think we think TL1A could be an a very attractive combination target as well, granted less certainty about the long-term safety and efficacy of TL1A as a class than the other two that we're talking about. Understood. Now, Cameron, I wanted to hit on something. I think you're gonna get into kind of a difficult question. It's not a bad problem to have, but whenever I talk to you, and frankly, when I even talk to the Apogee team, there's a lot of confidence that within one or two cohorts with your healthy volunteer data, you get to target exposure. Now, you know, I think there's gonna be a symphony of data releases, and you're gonna have to make kind of this decision as you move into phase II. Am I going to move in with a combination approach, go with the core formulation, starting all the way in phase II, especially if you don't have overlapping toxicity? Mm. Or do I go with monotherapy trials, and then once you find those doses, then go into the combination approach? Talk to me about the decision-making on that approach. Why would you maybe not go with just the monotherapy approach and go with the combination trial as early as a phase II study? And if that's gonna be the case, when would we find out? Yeah, so- from your team? Yeah, so I think kind of a couple of those things. So one, from a preclinical combination development strategy, we know that we need to show individual tolerability of these agents and then potentially test them in combination tox as well. The nice thing that we disclosed in our last quarterly filing is that our first molecule had the highest dose tested in the tox study was the NOAEL. So the idea of overlapping tox is hard to imagine when the first one has no observed- Mm A dverse effects. This is your Entyvio? This is the α4β7, had the highest dose tested was the NOAEL, so there really cannot be overlapping tox when the first one has no observed toxicity in the study. So that's a really good place to start. In terms of where we go in terms of combination development, the other place I would start is, what do we need to show for combination therapy? And again, we have to look at VEGA and DUET and understand that for combinations to be developed, you have to show contribution of components. You have to show that the combination is superior to the two monotherapies. Right. So therefore, to develop a combination, you functionally have to develop the monotherapies in parallel as well, and we think that's the right study to run for phase II, a study that includes both the combination and the monotherapies. You're advancing them in parallel, unless you, at the end, have a reasonable comparison between the combinations and the monotherapies, pick the winner to move forward. Okay, that's really interesting. And that would kind of put you in a position where I think in certain of these combination studies, you would move meaningfully ahead versus - I mean, these are obviously very competitive spaces. I wanted to hit, though, on DUET and how that could affect your decision-making 'cause, right, no overlapping toxicity. Your team seems pretty confident that at least from the IL-23 and Entyvio side, we're not going to see that dynamic. Great, that's a big deal. What do you think we're going - You know, how would differences in efficacy in this kind of biologic experience population affect your decision-making, right? Mm. If we see VEGA, I think that's- Yeah P retty obvious. What if you only see, you know, 5%-10% higher responses in the combination approach? Would you pursue the combination strategy as long as safety is okay- Yeah ... in some of these indications? So I think the question. So going from a naive population to a refractory population, the numbers are all gonna come down. Right. I mean, I think we've seen these individual monotherapies tested in refractory and naive populations, and we know the response and remission rates are lower in refractory patients than naive patients. So the monotherapy numbers, I think we have high probability, are going to come down. Question is, what happens with the combo arm relative to those? Sure. It will come down, too. I'd be shocked if it doesn't come down. Question is, does it come down to the additive of the monotherapies or something different? I mean, the challenge with this study in VEGA is that they didn't do what I think other studies have done, which is a 50/50 population and what our base case would be, which is a roughly 50/50 naive and- Right ... refractory patient population. Depending how DUET reads out relative to VEGA, I think we could decide to make an adjustment to that. But we already know in 50% of the population, the naive population, the combos have dramatically good efficacy. So I think you... I would have a hard time saying a DUET readout would dramatically change our position from an efficacy perspective. And on a safety perspective, we don't have a TNF, and so I think that's if you see TNF-related safety issues or something incremental, I'm not sure that if you swap out TNF for α4β7, you would actually have the same concerns. Mm-hmm. α4β7 doesn't have the TNF class safety effects, so- Just to put a finer point on that, would that mean your combination strategies, you may not get some of the black box warnings we've seen with agents there? Where's the base case? I mean, I would be surprised if any TNF-containing combo doesn't include the TNF black box warning. I think that is the kind of base case. The question is, do you get incremental concerns with TNF and an additional agent, or is it just TNF? And I think that we need the studies to find out, α4 does not have the same risks- Mm ... that TNF has, neither does p19 IL-23. So I think the base case monotherapy labels would look different than a TNF would. Understood. Now, you know, I think not everyone will share your view on overlapping toxicity, especially I think on the big pharma side. I think there is some... You know, there are people who are like, "Look, there's this kinda hazy FDA guideline of novel drug-drug combos and not having to run this kinda lattice approach, where you have to have different doses for both compounds. A big part of that is no overlapping toxicity. What does that actually mean, right? Like, as you get into humans, and you define overlapping toxicity with an IL-23 versus toxicity with your Entyvio, right, what are the different AEs that you expect to see individually with both drugs? Mm-hmm. What threshold in terms of an increase in AEs would be like, "Oh, this is overlapping, overlapping toxicity?" I have no idea. Yeah, no, I know. I think, I mean, so it's a good question, and I actually, I don't think there's a definitive answer- Yeah ... at this stage. We're kind of, this is, this is new territory that the entire field is entering, and it's not just us thinking that this is the future. I think every large pharma in this space, whether it's with Takeda, AbbVie, J&J, Gilead, are all announcing combination development strategies here. Sure. So everyone is kind of puzzling through this together. I mean, I think the question is, if we have the level of efficacy that's been observed with VEGA, what level of tolerability difference would be enough to change it in terms of your—you could have a JAK-like profile, where the efficacy looks really good, but the safety doesn't. Right. These products still have a place, but not the same place as if you had that efficacy without that, that safety issue as well. So, I mean, the reason why we're excited about this portfolio is that it has a possibility of delivering that efficacy without the black box effect of the TNF combinations, and then doing it all on a quarterly basis, which I think—I mean, I, well, I'm pretty sure we're the only ones that have the ability to do that, where we have all extended half-life antibodies on targets that we think have a lower safety risk. We can dose these things, hopefully quarterly, on both antibodies, whereas I think a lot of these other combos we're seeing are a mix and match of- Right ... not just different dosing intervals, injectables, but mixing and matching injectables and orals, which is, no, no one wants, people don't wanna take pills or injectables. Having to take both is worse than either. Understood. Look, I do find it kind of amusing that people are developing bispecifics for kind of soluble targets. There's not gonna be an avidity benefit there. You're just gonna not maybe inhibiting both targets properly. But when you think about the co-formulation approach, right, you've talked about each molecule separately. "I can get into a nice 2 mL auto-injector." I think the question investors have is: would you be able to maybe do one single dose with both approaches, or is this like a, I don't know, like a CagriSema type- Yeah ... dual-chamber injection? Well, when are you gonna start exploring that? Is that stuff that you're gonna have- Yeah ... potentially even in your phase II studies? And what's really the reasonable base case assumption for a combination Spyre drug delivery? So what we're doing now is selecting antibodies for development that can be co-formulated. It's not guaranteed that you can just take two antibodies in their formulations and put them together and dose them together. Right. So we're picking antibodies that we know are stable in the same types of formulations and highly concentrable as well. We have a 200 mg per mL solubility of our co-formulation between our α4 and our TL1A molecules already. We can show that we can get high concentration co-formulations of these antibodies, and we'll do the same thing with our IL-23 selection as well. First, that's what we're doing, that we can put these together at high concentrations. We, of course, don't know our doses yet for these agents, so we can't tell, okay, if we have 200 mg per mL of a combination, what's the total volume that we're going to need? That's something that we haven't addressed yet, and I think you're kind of addressing the range of answers, which is that if you're under 2 mL, it's an auto-injector. If you're kind of somewhere just above that, you could choose to do two auto-injectors, and then if you're a larger volume, then you would go with something like Skyrizi, uses an OBD, which is an on-body device. Mm-hmm. I think that's really the range of answers that we won't be able to address until we've selected doses for each of these products. All that said, in our phase II study, we're planning to co-administer these antibodies like J&J did with VEGA, separate administrations of the two antibodies. So we think that kind of really, this product development, device development is probably a more like a phase III question than a phase II question. Understood, and totally makes sense. Let's hit on the amount of readouts that you have coming out. 'Cause I think, legitimately, I think investors are like, "Okay, Spyre seems like a combo approach, and you'd understand what are they gonna get data on how many volunteers that makes them feel comfortable- Yeah ... quickly, that they have target exposure? Then for not only the Entyvio, but then the IL-23, then when do they make the decision, "Okay, with these phase II trials, we're gonna be able to run a combination approach"? That sequence of events, I think- Yeah ... is not really well understood right now. Talk to me about what we should be paying attention to. Yeah, I think it's a faster cadence than I think is generally appreciated, which is that these programs are on the order of a quarter apart in terms of their timing between these three programs. We'll be dosing the α4 program in the next few weeks here, and then the TL1A, second half of the year, and the IL-23 in the first half of next. They're approximately a quarter apart, and then the readouts will be staggered approximately the same way, ± a month or two as well. So really, over the next 12 and a bit months, we're going to have a cadence of three phase I data sets that hopefully will illustrate that we have what we think are both interesting monotherapies, quarterly plus versions- Right ... of things that are out there. But then, from my perspective, very interesting building blocks for combinations that will have high probability, will push the convenience bar, and I think at that point, we'll know that we can push convenience. And then I think the bet at that point is, okay, which, if any of these combos, deliver that additive efficacy, hopefully without any incremental safety concern, which I think multiple of our combos have the possibility of demonstrating that. Understood. Now, when we think about TL1A, you're talking about, you know, the Entyvio IL-23 as maybe more an ideal combo partner, but that leaves the question, okay, but TL1A is there as well. A, is there something that you would see maybe from your peers or internally that would make you feel comfortable about going with the combo approach with the TL1A molecule? Yeah. So, I mean, I think we look to three different types of evidence for the combinations. I have a genetics background, so that's the place that I often start, and we have either loss of function or reduced expression genetic variants that mimic all three of these targets, and we know that individuals are protected against IBD when they have any one of them. They're more protected if they have two of them. So we start with that and say, "Okay, there's human genetic evidence that hitting these targets together is compelling." Second is animal studies or in vitro preclinical studies. There's published data on both α4β7 and IL-23 together. There's also published data on IL-23 and TL1A together, suggesting that there's synergistic effects- Right of those as well. Then the last set, which I think is maybe a little bit more challenging, is like gonna be analogous clinical studies. So VEGA, again, like TL1A is in the same family as TNF, and TNF and IL-23 we know work really well. TL1A plus IL-23, I think we would have a pretty good assumption that works. The other good combination study that's out there is the EXPLORER study, which was α4β7 plus TNF- Yep plus methotrexate, and that also looked very good. So I think, again, we kind of have combinations here that are close, and I think for plausible reasons, better than the combinations that have been tested. They don't include that TNF, but they're in the same family with potentially more interesting data sets. So I think there's a pretty compelling package of data that suggests that these things have reasonable probability. Okay, so we shouldn't rule out TL1A in the combination? No, absolutely not. Absolutely not. No. Okay. DUET, this is more of a blocking and tackling question, but it gave me a lot of paranoia. I think on clinical trials, initially, this thing was supposed to read out mid 2024. Yeah. Then you reach out to J&J, and they're like, "No, actually, that's- 2025. 2020. Oh, 2020, I think. Yeah. Yeah. Now, now they changed it. Yep. But, talk to me about what you've seen. When is DUET reading out? What data do they maybe have already right now? Yeah. 'Cause again, it's gonna be really critical for your own development. Yeah, I mean, I think it's a one-year primary endpoint for that study, which means, and I think they've said now the trial completes first half of next year. I think pretty good indication that they're done enrolling that study, meaning they've had last patient in. They'll, a year from now, have last patient, last visit. I would expect data from them thereafter, some however many months it takes for them to clean that up and release it. So those are big studies. Like, the enrollment- Yeah speed when we look at it, it's not that bad, frankly. It's—I think it's a pretty good enrollment speed. There was quite a bit of enthusiasm for that just at a couple of the conferences. And, I mean, physicians were certainly excited about getting patients into that study, not just for the combination possibility, but also a lower placebo rate because they had multiple dosing arms versus the placebo. And we think we can learn from that in terms of why there was enthusiasm for that, in terms of how we design our studies to also mimic that enthusiasm for the combinations, enthusiasm for a low placebo randomization rate- Mm as well. I think we can learn from that and hopefully match it, if not exceed that. Understood. Now, with, you know, Paragon, there's always potentially other molecules that you're gonna get added into the clinic. Okay, you like the IL-23 in combination with Entyvio. You have a lot more safety data. So clearly, there's a benefit for looking at targets where there is a lot of safety data that you can rely on, especially when you're hitting kind of these I and I immunosuppressant targets. There will be more, I'm sure, programs from Paragon that will get added under the Spyre umbrella. Talk to us about targets that you're interested in, particularly in GI-related conditions, that, A, could either play well with your TL1A or, B, could have a standalone role that maybe investors aren't appreciating. Yeah, so I mean, we do have a fourth molecule that we haven't talked about as much, kind of in a—I think it's in a similar vein of where TL1A was a couple years ago, where reasonable genetic evidence, reasonable preclinical evidence, but no clinical evidence yet. And again, for this kind of combination-heavy development strategy, we don't really wanna be proving a new monotherapy biology in a combination study. That's really not the optimal scenario. Right. So I think in general, the idea here is, is not testing new biology in combinations, rather taking well-established biology and using that. So frankly, of the three, I think the three we have make the most sense. I think we'll have other things in the pipeline, but I, I'd be surprised if they're on the same timeline and something that we wanna test directly. Understood. I'm getting waved off. Thanks so much, Cam. Thanks, Scott. I really do appreciate it. Appreciation. Thanks to everyone for joining us.