Okay, good morning. We'll continue with the next session. I'm Paul Choi, and I cover the biotech sector here at Goldman Sachs. It's my pleasure to have Upstream Bio here for our next session. To my left here, it's Brian Sutherland. Maybe what we'll do is have Brian kick it off with a bit of an overview of Upstream, maybe a little bit of background on it, and sort of what the company's maybe special sauce is. Sure. Thank you, Paul. It's great to be here this morning. We really appreciate the invitation and the chance to share our story. Upstream Bio is a clinical stage company developing a monoclonal antibody antagonist of the receptor for TSLP. That antibody is called Verekitug. Verekitug is unique in the TSLP space in that it is the only drug currently in development targeting the receptor. All of the other drugs going after TSLP target the ligand. What we've learned as we develop this molecule is that the pharmacology associated with targeting the receptor is very specific and we think unique, and it confers upon the molecule. We think the potential to be differentiated in this space in really two ways. The first is potentially on efficacy, and that conclusion is driven by data that we've generated in patients with asthma and reflected in effects on key disease-driving biomarkers like Fe nitric Oxide. The other potential sort of pillar of differentiation is our dosing interval. Because of the potency of the molecule, we are able to dose this drug either every 12 weeks or every 24 weeks in clinical trials in severe asthma. If these attributes turn out to show themselves to be true in the clinical programs, then we think we have quite a differentiated molecule that will be a novel entrant in the space and hopefully helpful for patients. Great. Maybe just a little bit of background. Your company went public relatively recently, but it was private for a little bit as well. Can you tell us a little bit of background on how Verekitug was acquired and sort of developed? There is some background to it as well in terms of its involvement in development at large pharma as part of your ownership. Yes. Verekitug was actually discovered by Astellas. It was discovered by Astellas actually in the context of a collaboration with Regeneron licensing their VelocImmune technology to create novel antibodies for targets of interest to Astellas. One of those was obviously the receptor for TSLP. After discovering the molecule, Astellas actually did some very nice work both preclinically and in early clinical studies to develop the molecule. As we understand it, there was a strategic decision inside of Astellas to exit certain aspects of immunology as a therapeutic area. For that reason, the molecule was put up for sale. An early version of Upstream Bio was able to successfully compete for Verekitug at auction. We fully own it. We acquired it outright. We do have a total of mid-single-digit royalties to Regeneron for the technology platform and to Lonza for the master cell bank. Other than that, the molecule is completely unencumbered. We know we owe no milestones or royalties to Astellas. Okay, great. I think investors have some awareness of the TSLP space given Amgen's product is out there. Just maybe at a high level, if you could walk us through sort of the TSLP biology, its role and why you think versus what is already a proven commercial stage asset with tezepelumab, why you think there could potentially be advantages in targeting the receptor versus the ligand, which is the approach that other companies have taken. Sure. TSLP is a cytokine, thymic stromal lymphopoietin. It's a member of a class of cytokines called alarmins. You can think of these cytokines as sort of operating at the first line of defense. TSLP is expressed predominantly in the airway epithelium, and its production is induced by triggers, be they viral, environmental, or others. TSLP plays a key upstream role actually in initiating a number of critical signaling pathways that lead to what we sort of now think of as type II inflammation. TSLP sits upstream of IL-4, IL-13, IL-5, IgE, a number of other sort of critical and both clinically and commercially validated targets in the pathway. What we've seen with tezepelumab, which, as you mentioned, is a ligand-targeting antibody, is really a very nice clinical profile, one that meets or exceeds, in our interpretation, much of the competition in terms of clinical efficacy. That has really validated itself, we think, then commercially in terms of how successful that launch has been. Some of the attributes of targeting TSLP that play out in addition to efficacy are the fact that because of the breadth and sort of upstream nature of its position, patients, at least in the label for Tezspire, do not need to be classified by any kind of biomarker. There is a broader population. There is really quite significant efficacy. We think that those attributes come from the biology. Still see TSLP, and by the way, I think given the competitive landscape, a lot of others do too, still see TSLP as a highly tractable and interesting target. Now, what we've learned, as I alluded to as we've developed verekitug, is that when you target the receptor for TSLP with verekitug, you very quickly get 100% occupancy or blockade of free TSLP receptors. That then, when you look at disease-associated and disease-driving biomarkers like blood eosinophils and exhaled nitric oxide, is associated with significant and perhaps superior reductions in those biomarkers. Importantly, we see that effect both preclinically and clinically for up to 24 weeks after the last dose. It's really the potency of the molecule that confers upon it this unique pharmacology and again leads to these two potential pillars of differentiation, both on efficacy and dosing interval. I would just highlight that, again, we're the only known drug in development targeting the receptor, and the ligand-targeting approaches, as Tezspire has shown, can be successful. We think that there's still room to be better by virtue of targeting the receptor. That is the hypothesis that we're testing in our clinical programs. Okay, great. I want to ask maybe for a little bit of clarification on something you said earlier in terms of not being biomarker-specific disease. Did you mean by that by just eosinophilic-driven asthma or other subtypes or any other particular biomarkers? Yeah, so it's very much a biomarker-specific disease if we're talking about severe asthma in that the role of blood eosinophils and the biology that they reflect and the role of exhaled nitric oxide and the biology it reflects are very well characterized, very well understood, and I think across development programs in the space have been shown to be very important. The statement really referred to the label and sort of eligibility criteria not needing to be characterized by a certain eosinophil cut point. It is a labeling distinction that Tezspire has versus, for example, Dupixent, but it does not undermine the importance of these biomarkers in the disease. I want to follow up a little bit on your earlier comment regarding potentially quarterly or 12-week or 24-week dosing. Just roughly at a high level, can you walk us through beyond sort of the obvious advantages in terms of more convenience and in terms of the patient dosing schedule? I guess more at sort of a theoretical risk level, what are the risks or pros and cons of sort of that kind of long treatment duration or having the drug circulating in the system for that long and occupying the receptor for that kind of length of time? Yeah, so it's a really important question. It's one that we've actually spent a fair amount of time on, not just sort of elucidating what the pharmacology looks like, but why it looks like what it looks like and what that could mean. We've done some very interesting computational biology work really trying to model the system, if you will, and really model the effects of blocking signaling at the sort of cytokine level versus the receptor level. What we've learned is that there's, and perhaps it's obvious to some extent, the receptor is expressed at a very low level compared to the circulating ligand. There is a very vast pool of TSLP in proportion to the pool of TSLP receptors. The other thing that we've learned in our work is that the sort of refresh rate or the rate at which the receptor is turned over versus the ligand is also much lower. If you take those two things, you essentially have a situation in which it's very hard just sort of conceptually to give enough antibody to really block the entire pool of TSLP ligand and to do that consistently and for a long period of time. If you go after the receptor, even with an IgG1 like we have with a normal IgG1 half-life of about 18 to 20 days, it just takes so little drug because of these characteristics to occupy the receptor for so long that you can get to this extended dosing interval, we think, and get there in a different way. Everybody else who's doing extended dosing is by large extent doing it with Fc engineering and introducing the YTE modification, for example, to extend pharmacokinetics, but not necessarily change potency. That's how we get there. Now, what does it mean? Those are questions that we're asking in the clinical programs. We have a very nice and consistent sort of march of evidence from the preclinical space into healthy volunteers, into patients with T2 elevated asthma, and even into now the sort of pharmacology and computational biology modeling that has been very consistent, has really shown consistently this differential potency and has not, on the flip side to your question about risk, shown any meaningful difference there. We're at early days in the program. We're obviously monitoring this incredibly closely. By virtue of having an asset in the space and in the pathway in specific with tezepelumab, what we've seen is that in general, aggregating TSLP signaling seems to be very safe. The label for Tezspire is very clean. Tezspire is very clean in that regard. We would expect and hope to have a similar profile, but of course need to do the work to prove to patients and physicians that that's the case. Okay, great. Maybe diving a little deeper into the biology, I think some of the work you guys have shown has shown a few reductions, but can you maybe help us understand how you think about that versus eosinophil changes and what are, I guess, KOLs and physicians more focused on primarily here? Maybe just to summarize the evidence that we're basing all of this on, Upstream has done a multiple ascending dose trial in patients with asthma. Those patients were enriched for type II activity both either through elevations in exhaled nitric oxide or blood eosinophils. In sort of the typical escalating dose or dose regimen, in our case manner, we've been able to identify that we are really able to, again, fully occupy the receptor at the first measurement, and that was at two weeks, and then continue to really have that effect for up to 24 weeks after the last dose. We did that assay that I'm referring to, the receptor occupancy assay, using blood cells from patients in that trial. We then, in those very same patients, looked at changes in their blood eosinophil levels and changes in their exhaled nitric oxide levels. Really independently of where we started in terms of baseline, because these are small cohorts of six patients on drug and two on placebo in each cohort, we see that in association with this complete and sustained receptor occupancy, you really have very rapid and sustained effects that very much mirror the receptor occupancy on blood eosinophils and exhaled nitric oxide. Now, the magnitude of these is pretty substantial when we compare it versus what was observed in some of the Tezspire studies. It's actually greater, particularly from the sense of or from the standpoint of exhaled nitric oxide. It's on that basis, both in terms of the observed empirical data and the PK/PD modeling that we've done subsequently, that we believe that our effects on exhaled nitric oxide could be greater. Those really translate to a magnitude of effect that, at least in the modeling situation, is about 50% greater than observed with Tezspire in the clinical programs. Importantly, when it comes to potency and determining, say, the EC50 or EC90 for verekitug as it relates to exhaled nitric oxide, really almost a 300-fold greater degree of potency. Again, we need to, there are a lot of, it can be fraught to do cross-trial comparisons, and we are talking about MAD studies versus a much more robust program that Tezspire has done. We need to now test this in clinical programs, which we are doing. What KOLs are saying to us is that, okay, this looks interesting, prove it in a larger and better study. Obviously, we are doing that. I think what we've learned and what I think most KOLs would agree with is that there generally tends to be, if not a purely linear relationship between degree of effect on exhaled nitric oxide and clinical outcomes, at least sort of an ordinal one, such that a greater magnitude of effect on FeNO as a disease-associated biomarker is very nicely correlated with a greater degree of clinical efficacy. On eosinophils, it can be a little bit different. It's important to note, I think, that the IL-5 targeting agents, for example, are actually eosinophil depleters or eosinophil lytic. They can actually knock eosinophil levels down to zero, depending on the patient, depending on the disease, and depending on the extent to which EOs are really driving the biology in one patient versus another. There are certainly patients for whom those drugs work quite well, but they do it through a slightly different mechanistic approach and yet on the flip side have no effect on exhaled nitric oxide. It is complex biology. It varies a little bit. That is why we think being Upstream and actually having this broad set of effects across multiple pathways is the most efficacious way to go after these diseases. Just on that last point, why do you think you guys are having this pronounced effect on FeNO and eosinophils, whereas tezepelumab seems to be only affecting eosinophils? Yeah, I think Tezspire actually does have some effects on exhaled nitric oxide. I would probably, again, it's a little bit fraught. We need to see our phase two data before really doing direct comparisons. I think it's important to note that in Tezspire's context, targeting TSLP is very efficacious. That drug is a good drug. It works in a broad population. We think that that's, again, reflective of the underlying biology. Some of the mechanisms that other approved drugs take will result maybe in differential effects on EOs versus FeNO, but in general, both of these biomarkers are very much correlated and related to disease. Okay. I guess as you look at the broader landscape as well, another agent that I think investors are tracking is mepolizumab, excuse me. Mepolizumab. Mepolizumab, yeah. I guess as you think about the clinical development and treatment paradigm evolution over time, do you think about physicians or KOLs maybe thinking about one agent for one asthma subtype or phenotype versus others? Just how do you think, I guess, the differentiation among the various subtypes of asthma might affect preferential behavior in terms of prescribing? Yeah, I mean, I think that it's important to note that to some extent, the label for each of these drugs really drives sort of what payers will support, what physicians can do. I think if you were to just, rather than singling out a specific agent, let's just talk about IL-5, IL-4, 13, and TSLP, I think what you see are differences in the labels in terms of who was studied in the trials and therefore who the labeled population is. You see differential degrees of efficacy, perhaps because of the underlying biology. That is true in severe asthma. It's true in chronic rhinosinusitis with nasal polyps. As we get more and more data and labels that include COPD, the same will probably be true there. Physicians will make a decision, I think, on a number of things. Now that we've got sort of a palette of really good options that work, some of which work differently or more effectively and some of which work more broadly, physicians can really start to take both individual patient characteristics and convenience into account. On the flip side, we're talking about all this biology like it's exquisitely understood and really thought about and sort of incorporated into daily clinical practice. I think the reality is a lot of physicians don't always have all of these data that we're talking about, don't always have the time to work through this. We do see, I think, a world in which broad eligibility criteria, class-leading efficacy really do drive prescribing behaviors. We have some market research to also suggest that's true. When we actually do our market research and go out and talk to both patients, physicians, and payers, what we see actually is that once you've gotten to a world in which there are these highly efficacious drugs, that's where dosing interval actually really does start to play an important role in choice-making and on the commercial side, potential value creation. I think we're actually, we spend a lot talking about the comparative effects that we may or may not have on FeNO and exacerbations. Even if those turn out to be sort of tezepelumab -like, if we are able to conclusively show that we can deliver that at Q12 or Q24 weeks, it's really very much a game changer in our market research context in terms of how physicians make choices. It's been great. I've been working in this field a long time. It's great to now have gotten to these efficacy frontiers that are really significant and so much better than what can be delivered with inhaled therapy alone. Now we have the opportunity to start thinking about individualization of therapy and also providing convenience that goes from daily or more than daily therapies to maybe twice yearly. That's a huge advance. Right. One follow-up question to that is, as you look at the marketplace, from what you can gather, where is Tezspire typically tiered and how is it among payers and how is it typically sequenced versus other sort of standard of care options in the asthma space? I had a follow-up question. Yeah. I do not have specific data on specific products. That is probably a better question for the companies. I think what we have learned, however, is that in general, these drugs are roughly priced the same. They are roughly priced at parity. For that reason and because of good efficacy, but also some of the nuances that we have talked about, for the most part, our understanding of the landscape is that payers essentially sort of treat everything the same and therefore let physicians make the decisions that are appropriate for the patients. We would expect that dynamic to continue. It is actually an important context for how the market has behaved historically and how we think the market could behave going forward. One key aspect of that behavior is that, again, even though there are now six approved biologics in severe asthma, what you see is that, and let's just take Tezspire as an example, if you're differentiated either on efficacy, eligible patient population, or something else, you can come in and you can actually drive penetration. By doing so, you actually increase overall market share. You provide a very good commercial opportunity as a differentiated product, and you gain that opportunity simply through driving penetration mostly rather than eroding the share of others. We've heard some of our potential competition quoting rates of still less than 20% biologics penetration in severe asthma. There is a large opportunity there in terms of getting these drugs to patients who could benefit from them. We strive to be one of these potentially differentiated drugs that can come in and compete a lot of this dynamic. Yeah. This is a bit of a multi-axis question given that you're looking at asthma and chronic rhinosinusitis with nasal polyps. Just in terms of a potential product profile that could either be dosed quarterly or semi-annually, are you thinking about this ultimately as a self-administered biologic or something that would be administered in office by a provider? How does that, I guess, generally line up with the typical patient visit schedule for either condition? Yeah. So it's an important, I'm glad you asked that both about CRS with NP and severe asthma. Yes. Yes. That's the multi-axis, yeah, considerations. Yeah. In that the answers may be a little bit different for both. Let's start with severe asthma. In both cases, our aspiration is to come to the market with a prefilled syringe and an auto injector. That gives some optionality for in-office dosing or at-home dosing. If you look at what the competition is doing, it's very much aligned with auto injectors sort of being table stakes. We need to be able to launch with that. We have made investments and are working to do that. In my practice, when I was seeing severe asthma patients, once I got them controlled and everything was going well, I would see them every six months. It just happens to be the case that, yes, a Q6 month drug, I may not need to administer that in the office, but my treatment decision, the continuation of that prescription, et cetera, could very much line up with a standard dosing regimen if we can get to Q24 weeks. Now, in the case of NP, there may be an opportunity in that disease for both in-office administration and at-home administration. In our trial that's ongoing right now, we're only testing the Q12 week regimen as a first step in CRS with NP. We won't have Q24 week data potentially until that program is fully through phase three. Yes, a Q3 or Q6 month dosing interval would be very consistent with how often these patients are seen. Again, we think would be quite differentiated versus competition. Okay. Maybe turning to the chronic rhinosinusitis program, can you maybe talk a little bit about how your phase two enrollment is going there? I do not know if you've necessarily guided the market to this, but just how do you think about guiding the street to last patient, last visit timeframes for that program and the asthma program? Yep. Enrollment is complete in our nasal polyp study. We have guided to Q3 of this year for data release and are on track to do that. In terms of what we're going to deliver and what we're going to be talking about, I think it's really important to just dive in for a minute into the trial design. Our trial is 100 mg of Verekitug delivered Q12 weeks versus placebo, one to one. We have designed that trial to basically rely on regulatory enabling endpoints. We have the endoscopic nasal polyp score as the primary endpoint. The nasal congestion score is a key secondary endpoint. There are others in there as well. We have powered that trial to basically detect a dupilumab-like effect or greater. This trial, if positive, has been designed in a way that, and by the way, following a regulatory path that already exists, to allow us to potentially go to regulators and discuss using this as one of two registration enabling or BLA supporting trials. It is a very robust phase II- B-like trial, looking at the key regulatory endpoints with sufficient power to detect a significant difference. We are really excited to see this as sort of the first step in our data as it relates not only to comparative efficacy, but also dosing interval. We think that if we can deliver a tezepelumab-like effect at Q12 weeks, that is a pretty good profile. If we can beat on efficacy, that is even better. This is all speculative until we have the data. We will be looking very closely at that. The endpoints, endoscopic nasal polyp score and nasal congestion score are very robust. They're very well validated, very well understood. Even though we sometimes get the question, well, it's a smaller study, 70 patients, that's still sufficiently powered to be able to detect an important difference. Can you just remind us, are these dupi experienced patients, dupi naive, or a mix of both? Yeah. Patients cannot have had biologic exposure within a certain period of time prior to entering the study, but we are not excluding patients who have ever been exposed to a biologic. Provided they have the sufficient washout. Yes. Okay. Great. I guess in terms of the competitive landscape, there are also some orals that are in development here, including Chimera. I guess as you think about the role of orals here in the space, how do you think about what challenges or advantages they may present to your program? Yeah. I mean, we've been really impressed by Chimera's data. They are daily administration of an oral agent that needs to be translated from healthy volunteers into disease, et cetera. We're happy to see, obviously, the suite of options continuing to grow. It's been one of the greatest things about this field over the last 20 years. I think there will be questions, and actually these are questions that we're testing right now in conjoint market research around what is the trade-off between oral convenience and Q6 month convenience when it comes to an injectable. I think my view would be that efficacy will continue to lead. Breadth of eligibility will continue to lead. We'll be understanding the crossover between oral and injectable in terms of convenience. It probably is somewhere beyond daily, just based on sort of extrapolation from other fields. It would probably require oral agents to get to weekly or monthly, even or semi-weekly before it starts to be a significant threat. That is, again, pretty early days. We are generating the data to be able to answer this question better over time. Okay. Great. I guess you mentioned something earlier, which caught my ear, which was that you talked about aligning on the regulatory endpoints. I guess down the road, though, do you think either a head-to-head study versus dupi will be required just for market differentiation and/or payer considerations? Yeah. I mean, typically it's the latter, right? Payer considerations, maybe more in Europe than in the U.S., that those kind of requests come. Sure. We have not encountered any of those requests yet. I think the first principles are still efficacy versus placebo. The second will become efficacy versus other agents. That is a down-the-road question for us. It is not one that we are contemplating currently as part of our development program. Again, there probably is some just relative efficacy differential doing cross-trial comparisons that once you cross it, you are going to drive share. What that is and how that landscape is going to change over time is TBD. Right now, from the regulatory perspective, independent of the comparative question, there is FDA guidance on what the endpoints need to be for a nasal polyps program. We are following that and incorporating that into our program. There is a long history there as well in NP. The same is true in severe asthma. The same is true in chronic obstructive pulmonary disease. We are blazing new ground in terms of our molecule and what it does and how it's different and understanding the biology associated with it. At the same time, we're following a pretty well-trodden regulatory path when it comes to biologics in these diseases. That's a great position to be in. Great. Maybe as a follow-up to that, can you maybe just remind us how the EU and/or Asia regulators think about these diseases and developmental paths? How does your clinical plan potentially satisfy those regulatory parameters in ex-U.S. markets? Yeah. I mean, with the caveat that we've not yet had these discussions, I think we feel quite good that our plans would be globally applicable. Okay. Cool. I guess with the chronic rhinosinusitis polyp data not too far off in the future here, after you topline, is there a medical meeting where this would potentially make a lot of sense to present in detail? Yeah. The answer is yes. Which one depends a little bit on timing. The late breakers, even those abstract submissions happen months in advance. Whether it would be a meeting in early next year or mid-next year, I think would be to be determined. There is a big allergy meeting, QuAD AI, in typically February, March. There is ATS in typically May. Those could be potential venues. Okay. Great. Which would, of course, follow press release and other discussions about the data. Sure. Oh, just on that, would you have a post-end of phase two meeting prior to your medical meeting presentation, or would that kind of? We haven't disclosed our regulatory strategy, but that would be, I think, pushing it. Okay. Got it. I want to talk maybe in our time remaining a little bit just on COPD plans and just sort of how you think about the landscape there. It's often a holy grail for development of drugs in this area, just given the market opportunity and size of the prevalent population. Just maybe in broad sketches, how are you thinking about your COPD plans here? Yeah. I mentioned how great it's been to see things evolve in asthma. It's really been even, I think, greater for me to see the evolution of biologics now coming into COPD as well, because it's been a tough disease to treat and obviously just globally has a substantial impact. The first principle of just seeing this biology now being translated to COPD has been really important. I think it opens opportunities. Dupilumab is already going to start leveraging that. We've seen some of the IL-5 starting to come in. We, I think like others, were pretty excited by the tezepelumab COPD phase two data that were released now about a year ago that suggested that TSLP modulation could have an effect as well. Furthermore, that seemed to be sort of associated with degree of type II inflammation. You'll recall from those data that in the eosinophil 150 and higher subset of patients, there was evidence of a significant reduction in COPD exacerbations with Tezspire. We have looked very closely at that and I think would take a similar approach in the design of our trial, really focusing on that 150 and up population to test one or more doses versus placebo. When you dig into those data, you see that there are potential signals of efficacy even at the 150 and below eosinophil cut point or subpopulation as well. We want to be able to explore that. There is at least a hypothesis that our potency could translate to differential efficacy in that group. We will be designing the trial and executing the trial in a way that allows us to explore potential efficacy in that subgroup as well. Okay. Great. We're coming up on time here, so I want to talk a little bit about maybe some corporate considerations, which is just in terms of your capital position and your cash runway. Can you maybe just remind us where you stand, at least as of last quarter, and how your current phase two plans are figured into your cash runway? Yeah. As you mentioned at the top of the discussion, we went public in the fall of last year. We just reported $430 million in cash at the end of last quarter. That actually puts us through 2027 in terms of cash runway. I think even more importantly, contextually, it puts us through our nasal polyps readout. It puts us through our severe asthma readout. It puts us well along into the initiation and execution of COPD and also funds substantial investments into CMC and device development. We are in a fortunate position that we can operate a little bit independently of the market chaos right now. These indications are large. They take substantial capital. We will be needing to raise additional funds over time. Right now, we are in a very strong position. It looks like this takes you pretty much through your mid-stage development plans and maybe some of your early registrational efforts as well. I guess as you think about longer-term development, I guess, and advancing to the registrational and commercial stage, when do you start thinking about commercial considerations as well? You talked a little bit about developing the device. Obviously, that takes a little bit of runway as well. Framing out and thinking about your commercial efforts and/or potentially partnering at Verekitug. I mean, the answer is now. We're already thinking about because where you end in the market obviously starts at the preclinical stage. We're very much testing TPPs that we think are robust, differentiated, and again, would support substantial opportunity. That's work that can start early, but then needs to be supported by more and more commercial expertise, market access expertise, medical affairs expertise, launch planning and execution. We are in the very early phases of starting to think about that. We will need to bring on additional talent and leadership to the company over time to enable that. We understand the markets we're working in. We understand the competition. They're very good and have been doing it for a long time. We need to be prepared to give the asset the best opportunity. I think in terms of partnering, it's a little too early to comment. We are routinely talking with strategics as part of a normal course of business and learn a lot from those in terms of the feedback we get from those conversations. At the right time, depending on capital and other things, could make decisions to partner, not partner, or something in between. Okay. Very good. We're exactly at time right now, so I'm going to stop it on that note. Perfect. My thanks to Rand and Upstream for joining us here. Yes. Thank you very much.