Conference. My name is Yasmeen Rahimi. I'm a Senior Biotech Analyst here at Piper Sandler. Excited to have the team from Upstream Bio with us. Lots to cover over the next 25 minutes. I think. Congrats on a great IPO, and it's been a pleasure covering your name, and I've had the pleasure of backing the company for a while and seeing the tremendous progress that you guys have made, so. Yeah. Well, thank you, Yaz. It's been great. We've had a good time, and I really appreciate having the opportunity to speak with you today. No, that's wonderful. I think a lot of investors, that's based on discussions, it comes, it's very clear, you know, like they look at Upstream Bio with Verekitug, a differentiated mechanism. Mm-hmm. That is de-risked, right, from a regulatory perspective based on the mechanism for. Mm-hmm. Respiratory and inflammatory diseases, but I think the question that comes up, and which you're getting consistently, is differentiation of targeting the receptor versus the ligand, right? Right. If you could just maybe talk briefly around what we have learned in terms of the benefits of receptor targeting, and why that's so critically important, let's maybe start there. Sure. No, it's a, obviously the key attribute of our molecule. So Verekitug is a monoclonal antibody. Mm-hmm. As far as we know, it's the only drug in development that targets. Mm-hmm. The receptor for TSLP. Everybody else leveraging this biology is going after the ligand. And what we've learned about the molecule is that targeting the receptor confers a very specific set of attributes. Mm-hmm. To the molecule. What we've shown in preclinical and now clinical data is that, very rapidly after administration of the molecule, we get complete occupancy of the free TSLP receptors. Mm-hmm. and that very clearly translates then to sustained and substantial reductions. Mm-hmm. In exhaled nitric oxide and blood eosinophils, and it's really this sustained part that's. Mm-hmm. That's very interesting. Our data indicate that, you know, after the last dose of the drug, we still have 100% TSLP. Mm-hmm. Receptor occupancy for up to 24 weeks. Wow. After that last dose, that then conforms to what we see with the disease-related biomarkers and, you know, has allowed us in our clinical program. Mm-hmm. In asthma to test both Q12W. Mm-hmm. Actually Q24-week dosing in our clinical trial. Mm-hmm. You know, I would point out that the way we get to this extended dosing interval is not through any kind of Fc engineering. Yeah. This is an intrinsic, I think, property of the molecule and of the biology itself. Yeah. You know, relative expression, for example, of the ligand. Mm-hmm. Versus the receptor turnover of those different targets. Mm-hmm. which again, together come together. Mm-hmm. Suggest the potential for differentiation not only on dosing interval. Mm-hmm. You know, potentially given our phase one MAD data on efficacy as well. Okay. And then, team, I think there's quite a tremendous number of companies. Well, it's not. The field of TSLP antibodies is growing. Mm-hmm. You're the only one that targets the receptor versus the ligand. Yeah. Could you maybe talk about and you have potentially, if not base case, three-month dosing, if not every six months dosing. How does that compare with other TSLP antibodies that are in development? Just if you could put it into perspective. Sure. You know, I think we all know Tezi's monthlies. Right. Administration, but others. Yeah. So there is an approved molecule in the space. The biology's been de-risked from that standpoint, which is great. You know, again, everybody else is targeting the ligand. Mm-hmm. and, you know, that comes with, I think, a very. Mm-hmm. Diverse and complicated landscape right now. Mm-hmm. As you mentioned, there are a lot of people going after the target. You know, we've tried to dissect it in a few different buckets. The first is those. Mm-hmm. Who are also pursuing extended dosing intervals. It's our understanding in general from those other programs that they are all achieving extended pharmacokinetics through engineering of the Fc. Mm-hmm. You know, often the YTE mutation that changes the pharmacokinetics, and then companies can make choices about how far they wanna push. Mm-hmm. The half-life in terms of making dosing interval decisions, and so, you know, there is a class of other competitors pursuing that approach. Mm-hmm. We again are differentiated by MOA, and also believe that we have. Mm-hmm. Substantial advantages just in terms of time and where we are. I'd point out that we are. Mm-hmm. You know, well into enrollment of our phase two trial in severe asthma. We'll be reading out top line from that in the second half of 2026. That's a robustly designed trial that is designed to potentially serve as part of a submission. Mm-hmm. Regulatory submission package. So, you know, we are far along in very well-designed trials. Others are less far along. Mm-hmm. And I would say that that applies not only to those that are pursuing extended dosing interval through Fc engineering, but also the whole landscape of TSLP targeting antibodies that don't have dosing interval advantages versus, say, Tezepelamab or others. Okay. Team, would love to kinda actually start the discussion on chronic sinusitis with nasal polyp just because that's the first readout. Yes. Then moving to the asthma. I think one question is, how big is the chronic sinusitis with nasal polyp market? Because there is quite a bit of an overlap with asthma patients. If you could just talk about the market opportunity there and. Right. Besides that, it could be helpful. Yeah. It, I mean, it's a very interesting question. Mm-hmm. Because I think the epidemiology has been defined in part in the context of, you know. Mm-hmm. Tezepelamab's launch and success in that space. Mm-hmm. and partly in the context of an environment where biologics eligibility was initially. Yes. Defined by having severe disease. Mm-hmm. Requiring surgery, refractory to. Mm-hmm. Surgery, etc. I think, you know, as we've seen Dupilumab, now other biologics and hopefully soon to be others coming into the toolkit for clinicians, you know, we may start to see a change in how medicine is practiced with surgery perhaps. Yeah. Becoming, you know, less important in defining eligibility and sort of first-line treatment. So, while we've used the 900,000 eligible patients figure that others have used in this space, we're watching closely because we, you know, would think that as medical practice changes and as more patients, sort of at the clinician and at the bedside level, become eligible for these drugs via individual prescribing practice. Mm-hmm. That we may see some of the guidelines and some of the other, you know, approaches to defining the eligible population change and perhaps make it even greater than that 900,000. Okay. And then team, the Tezspire 52-week Waypoint study. Yes. Was quite bare-bones. I think they said they had stats saying a nasal polyp size and reduced nasal congestion. What was your take on the press release? What stood out to you, in your view, like? Yeah. I mean, the first thing is we'll obviously see more at some point. Yeah. You know, maybe the next big medical meeting, which, you know, could be in the spring. But it was reassuring to us to see that, you know, they had, sort of gone about their program in a way that allowed them to use this sort of dual or sort of co-primary that's now required by virtue of the FDA's guidance, in this regard. So the fact that they hit the top line. Mm-hmm. I think it's good. It's good for their program. I think it's potentially good for patients. We'll see the magnitude of that. Mm-hmm. Effect. We'll be digging into all the secondary endpoints as well, and understanding what kind of label that might or might not support. Mm-hmm. But I think we see it as another step. Mm-hmm. Another de-risking step for the biology. Mm-hmm. In these diseases, as you mentioned, there is a lot of comorbidity. Mm-hmm. A lot of patients with chronic rhinosinusitis with nasal polyps have asthma. Mm-hmm. Vice versa is also the case. And so, you know, as you've seen happening with a lot of these pathway-focused drugs, there is the potential here. Yeah. For leveraging the biology to be successful across multiple different indications. Mm-hmm. That's a path that we intend to pursue, and we're happy to see that Tezepelamab has been successful in that regard, at least at the top line. Okay. And then, is there a mechanistically one can think about the advantage of targeting the receptor versus the ligand in chronic sinusitis that could make sense based on preclinical models that you could? Yeah. Predict a differentiated. I think we have to speak to our data. Yeah. You know, the preclinical data do suggest that there is a potency advantage. Mm-hmm. Versus Tezepelamab. The, you know, human in vivo data were all derived in our experience from the multiple ascending dose study in patients with asthma. Mm-hmm. And so we don't wanna extrapolate beyond that. Yeah. but we do believe, and it's important to note that differentiation. Mm-hmm. Just on dosing interval alone in our market research is a very powerful differentiator. Yeah. Actually drives a lot of theoretical uptake, even given a Tezi-like efficacy profile. We have a strong degree of confidence in our, not only our data, but our modeling that led to the dose selection. Mm-hmm. The dose regimen selection. We do believe that there's a strong potential. Mm-hmm. Although we are doing the trials, that we will be differentiated on dosing interval. Whether or not we'll be dosing, differentiated also on efficacy is TBD. You know, there hasn't been enough, I think, experience yet in biologics and NP to really know what some of the dynamic range of some of these endpoints is. Mm-hmm. but when you look at an endoscopic endpoint in the nasal polyp score. Mm-hmm. When you look at symptom scores, when you look at quality of life. Mm-hmm. When you look at radiographic data. Mm-hmm. When you look at in patients who have comorbid asthma, the effects on lung function, there is a lot of data that you can derive from these studies. Mm-hmm. And, you know, we'll be interested in digging deeply to understand how our data compare to those of others. Okay. Your VIBRANT study is in full gear mode. It's, you know. Full gear mode. Data is in second half. How is enrollment progressing when you need to kinda bring it to the finish line to have data on track? Yeah. Yeah. I mean, we've been pleased with the progress of the study. Mm-hmm. We've been pleased that we're progressing. Yeah. Sort of to the timelines that we've communicated, and we fully intend to, you know, deliver when we say we will deliver. Okay. And I think the other question that investors have is like, what do we wanna see, right? Because the study is, you know, the Tezi's phase two was not really a phase two. It was a subpopulation. And I think it's unfair to compare to Tezi's phase three just given the size. So what do you hope to see in Vibrant in terms of bar for success? Like, what do you yeah. Yeah. Or to establish, you know, a differentiated product profile that's become clear? Yeah. So I think the first point to make is that our phase two study, you know, the one you're referring to that's underway, is robustly designed. Mm-hmm. It's placebo-controlled. It's randomized. Mm-hmm. It's, you know, very adequately powered to detect a clinically meaningful difference. Mm-hmm. In the endpoints of interest, so, you know, a positive readout from this trial will be, I think, you know, a win for us. Yeah. We clearly need to be successful at the Q12 week dosing interval, which is the one we're employing in this study, and then, you know, again, we will see what our nasal polyp score and our nasal congestion scores are. Those are sort of the two most important. We've got a number of secondaries. Mm-hmm. You know, if we could beat on nasal polyp score and nasal congestion score. Mm-hmm. That would be, I think, a strong win for us. But, you know, we will wait until the data speak for themselves. Okay. When you talk to patients with chronic sinusitis with nasal polyp, is there a hierarchy of manifestations that are more important for them that they would like to see a benefit in versus others? Yeah. Yeah. I'd say that almost no patient goes around complaining about his or her nasal polyp score. Yeah. Right. What they complain about is not being able to breathe, not being able to sleep. Yeah. Not being able to taste. Right. Constantly feeling like their head is full. Yeah. If they've got asthma, feeling like that asthma is more difficult to control or more frequently exacerbating. Yeah. So, you know, I do think we're in this, you know, it's kind of a situation where you have to design your experiment with objective measures. Right. That you can, you know, see or not see depending on the outcome. But this is really a patient experience-driven disease. Yeah. As much as anything else. What is considered like a clinically meaningful difference in nasal polyp score reductions? I'll answer that by saying that we've powered our, Mm-hmm. Our clinical trial to detect a Dupilumab-like effect. Okay. You know, there's always the sort of universe of minimal clinically important difference and how you sort of go about determining what that is. I think in the case of, you know, marketed products where there are others on the market, you almost have to put yourself in their context. Yeah. So. What did they show like? We're powered for 85% to detect 1.5. Mm-hmm. unit or greater effect on the nasal polyp score. Okay. Perfect. And then, team, is there because chronic sinusitis is gonna come out before asthma, so sometimes investors, even during the roadshow, always talk and will continue to ask you, right, like, is there anything that we will learn? Obviously, the dose administration's gonna be critical, right? So if you have every six months dosing could be important for. Is there anything else we can learn? Like, can we look at a subpopulation of patients that have asthma? Yeah. That you're reporting out as well? Like, is there a read-through, I guess, from VIBRANT to? Yeah. I mean, I think the first thing to say is that if we hit our primary endpoint with the design we've employed with a Q12 week dosing interval. Mm-hmm. That will be a first in the field. Yeah. It'll be a first in general for dosing frequency and biologics in these types of diseases. And it will be a first in the TSLP class. Mm-hmm. That's important for us. I think in terms of the biology, what we've learned starting with Dupilumab and sort of working our way through others is that, the biology is so strongly interrelated. Mm-hmm. that there are often beneficial effects on these comorbid atopic diseases that happen as a result of treating another. Mm-hmm. So we can't yet say whether or not we see that. Our data will tell us. Mm-hmm. But, you know, I think there's the opportunity here to strongly de-risk really significant questions around the molecule, including dosing interval, overall efficacy in a disease where others have been successful, and to provide significant information about read-through because we are collecting. Mm-hmm. Data about comorbidities in this study. Okay, and then for the VALIANT study in severe asthma, that data is expected in the second half of 2026. Yes. How is enrollment progressing there, you know, in terms of, sort of execution-wise? Yeah. Making sure, yeah. I mean, as with nasal polyps, we've been pleased with the rate of progress. We continue to be on progress to deliver the data in the second half of 2026. Yeah. And, you know, there's been a lot of just anecdotal enthusiasm. Yeah. At sort of the site and investigator level about the program and about the molecule. Yeah. I think that's helped us. Okay. And remind us in terms of what the study is powered for. Yeah. That you wanna achieve here. This is another one where we're, you know, robustly powered to detect, sort of a Dupilumab-like effect in annualized asthma exacerbations. That's the primary driver of healthcare utilization here, and is our focus. Okay. It's also the focus of regulators. Yeah, and what is that treatment effect for so that people don't need to look it up? Yeah. I think we'd say that about 50%. Okay. reduction in exacerbations would be meaningful. Okay. Placebo-adjusted? Placebo compared to placebo. Okay. That's, that's helpful. And past the study, you're gonna get ready for a registrational phase. So I guess before we go there. Mm-hmm. A lot of investors are asking us, "you're powered for to Tezi's efficacy-like." You're targeting the receptor. You have FeNO responses that are double that was observed with Tezi. So one almost postulates, what is the correlation between FeNO to asthma exacerbation rates? Because what they're trying to figure out is like, can we infer that not only are you gonna have better durability. Yeah. But you could also be better in potency? And I like, one could argue in both ways, but I know that it's, that's not our base case assumption. Right. It's a best case assumption, you know, like, but would love. Yeah. Yeah. That comes up a lot, and I'm sure you guys get the question a lot as well. We do. Yeah. I think, I mean, you know, just to quote our clinical data from our phase one. Mm-hmm. You know, placebo-controlled, randomized. Yeah. phase 1 multiple ascending dose trial in patients with asthma. Mm-hmm. What we observed there was, and when we took the observed data and actually subjected them to modeling. Mm-hmm. What we observed was sort of an overall maximal predicted effect of verekitug. Yeah. On exhaled nitric oxide, as you mentioned, of about 1.5 fold greater. Mm-hmm. You know, and that translated to EC50s and EC90s that are substantially lower than those observed with Tezepelamab. What does that all mean? Well, a lot of that drives our ability to dose the drug as infrequently as we are. But we did see when comparing, you know, both from the modeling standpoint and the observed data standpoint. Mm-hmm. We did see evidence, again, these are early data and, you know, phase one and, you know, with all those caveats, absolute reductions in exhaled nitric oxide that were greater than those observed with tezepelamab. Mm-hmm. So to your point, what does that all mean? Well, the short answer is the data will tell us when we get the trial done. You know, it's kinda tricky because there's a very tight correlation between exhaled nitric oxide and disease activity, risk of exacerbations. Yeah. And actually treatment response with these, with biologics in general. But there's not sort of a straight linear algorithm either. Right. And so while we, again, do believe that there's a potential for us to demonstrate greater efficacy. Yeah. While we're certainly looking at patients who, you know, have a substantial exacerbation history. Mm-hmm. You know, we're still drawing conclusions from early clinical data, and I think it would be best for us. Yeah. To wait until we see the data, but hope and belief that. Yeah. It's in the realm of possibility. Is it fair to expect that your regulatory path in phase three would be very similar to the Navigate studies that, or do you expect sort of the? Yeah. You know, the design elements and the size? I think it's probably too early to speculate. Yeah. You know, we gotta get through the phase. Yeah. In the phase two meetings, I do think it's fair to say that there is very well-trodden. Yeah. Regulatory, a very well-trodden regulatory path. Yeah. With biologics in severe asthma in general, both in the U.S. and in Europe. Mm-hmm. And so you can look to the history and the experience there to inform. Yeah. What we would very likely do. Okay. But you know, the details matter in these things too, obviously. Okay. No, that's helpful. And then how do you think the field is gonna evolve in severe asthma, right? You have a successful phase 2b, you reproduce it in phase 3. How do you think the market dynamic is gonna evolve? Yeah. and usage and what market research have you guys done? So we've looked at a few different things. The first is just, you know, anecdotally in the space. Mm-hmm. We've got six biologics approved in severe asthma. Yeah. They're selling around $7.5 billion per year. Yeah. You know, depending on who you talk to, the CAGR might be 5% or 6% for the next decade or so. You know, that indicates a couple of things to us. The first is that new entrants, and if you look at Tezspire's launch. Yeah. Which has been fabulous, you know, new entrants can come in and they can take significant share. Yeah. It's interesting when you look at share proportionality, they do it not really by taking share away from others. Yeah. But by actually driving. Driving overall penetration. Yeah. And that's been true, you know, when Dupixent came online. Mm-hmm. It's been true when Tezepelamab, Tezspire came online. And so what you see is that novel MOAs that are associated with better efficacy. Mm-hmm. You know, can obtain significant market share. We don't see anything really disrupting that for the near term. Yeah. Just given the fact that biologics penetration now into eligible patient populations is only about 25%. Yeah. So we believe that the aggregate dynamics of the market will continue for the foreseeable future. What we are seeing now, you know, not just with our competition in the TSLP space, but even with Depemokimab. Mm-hmm. The GSK's long-acting IL-5 is that there clearly is a move now in the field to long-acting therapy. Mm-hmm. You know, right now we believe that we have the potential to be second to market. Mm-hmm. The second long-acting drug to market in severe asthma if Depemokimab gets approved. That'll be a good space to be in because they'll be out there helping get people comfortable, but you know, there's a lot of competition as well. But I do think, you know, if you've got greater efficacy and you can be successful at improving patient convenience and dosing interval, that's gonna kinda be table stakes. Yeah. For what success looks like in the future. No, that's helpful. And I think there's also a lot of pipeline opportunities as well. Mm-hmm. Developed in COPD. Yes. I think it seems like TSLP works in COPD. The question is what is the right population to enroll the study? Right. Would love to hear you guys have also said you were contemplating to expand into COPD. So what do you wanna see from the competitive landscape to then really commit into sort of a phase two study in COPD? Yeah, well, we've committed. Yeah. So we. So we've committed, yeah. But what do you wanna see to find? What are we? How's what's it gonna look like? Yeah. So we will be starting our phase two B in COPD. Okay. Sorry, phase two in COPD in the second half of 2025. It's probably a little too early to. Yeah. Get into the specifics, but, you know, we've seen that Dupilumab just got approved. Yeah. Their trials enrolled those who are 300 and up. We saw the Dup, Tezepelamab proof of concept data. Yeah. which suggested that at a lower eosinophil cut point. Mm-hmm. Maybe 150 and up, there was evidence of efficacy that was maybe even numerically a bit greater. Mm-hmm. than that seen with Dupilumab. You know, how to handle that sub-150 group. Mm-hmm. It's something that, you know, we're. Mm-hmm. I think many others are working through. We would like to study that population. Yeah. We would like to understand how our drug performs there. Yeah. But we also need to, you know, work within the confines of what's achievable in terms of study size and, just from an execution standpoint. And so, you know, exactly where we draw the cut point, how we power the study. Yeah. All that kinda thing is TBD, and we'll communicate about that at a future date. Okay. So for now, it's just trying to do your own market analysis and research to understand what's the optimal design, get the FDA's. Yeah. I mean. Yeah. This will be another one where there's a fairly traditionalist approach in terms of number of studies. Yeah. Exacerbations is the primary endpoint. Yeah. Lung function, quality of life is secondaries. A lot of that is not. Yeah. Defendable. Yeah. The real art here will be determining where, if at all. Yeah. To set an eosinophil cut point and then how to design the analyses around that. Okay, and then, team, obviously there's a few readouts for the bispecific, you know, or dual compounds to IL-7/TSLP. Mm-hmm. And AD and AA that's upcoming. So, you know, I think investors are trying to also wonder, like, if those studies are positive, can we be assured that maybe AA and AD are pathways that you guys could contemplate with? Or how do you think about, I know you have a lot on your plate. Yeah. We want more studies. Mm-hmm. But more indications, but. It is an important point that we are very execution focused at the moment. Yeah. These airways disease trials are big. Yeah. They're global, they're complicated. Yeah. So we are focused. Mm-hmm. I do think the question about atopic dermatitis is a really interesting one. Yeah. We know that Tezepelamab. Yeah. Had two negative. Yeah. Well-designed phase 2 trials in atopic dermatitis. We've seen some small open label data from others that maybe suggest a signal there, but those have not been, at least to us, compelling enough to warrant initiating a fourth. Yeah. Indication. I think we'd like to see what happens with some of those programs. There is, I think, an interesting hypothesis that in AD you may need multiple pathways. Yeah. To be successful, and so bispecifics targeting TSLP. Yeah. IL-13 and others are out there. We're following those closely. Yeah. For any insights that we might be able to derive in terms of making, you know, decision-making about next indications. Yeah. But to be clear, we have prioritized what we've prioritized on the basis of, we think, biological probability of success, technical probability of success. Yeah. Commercial opportunity. Yeah. Perfect. We have come to the 25 minutes and we covered all key topics. Right. Thank you so much for being part of our conference. Thank you.