Thanks once again for joining us at the 45th Annual TD Cowen Healthcare Conference. I'm Yaron Werber from the Biotech team, and it's a real pleasure to introduce Upstream Bio. The CEO, really, Rand Sutherland, really needs no introduction. You've been a KOL in this space for a very long period of time, a lot of experience in running both orphan businesses and a lot of experience in asthma. Rand, thanks so very much. We'll do a presentation, and then we'll take some Q&A at the end.
Yaron, thank you for the kind intro and for the opportunity to be here today. It's my pleasure to share the Upstream Bio story with each of you this morning. We'll save some time at the end for questions as well. We are a public company. We do have some disclaimers to share with you, and I will be making forward-looking statements. Having said that, let me begin by giving you an overview of our company and what it is that we are doing. We are a clinical stage company, and we are developing a monoclonal antibody called Virecetug for severe respiratory diseases. Virecetug is unique in that it is the only drug in development that is targeting the receptor for TSLP.
As I'll share with you, that confers upon the molecule some very specific pharmacology, which we believe gives us a basis for differentiation sort of in two important domains. The first being dosing interval, and the second potentially being efficacy as well versus the paradigmatic molecule in the space, Tezspire. Our data thus far generated from phase one have demonstrated a profile that is really marked by rapid, complete, and sustained occupancy of 100% of free TSLP receptors. That confers upon the molecule a very high degree of potency, which has allowed us in our clinical programs to test dosing intervals of every 12 weeks and every 24 weeks in our ongoing phase two program in severe asthma. I'll share a couple of our other indications with you as well.
Now, we have actually already demonstrated, we believe, proof of concept in asthma on the basis of our multiple ascending dose trial in that disease. What we've shown, particularly compared with a number of other biologics in this space, is differentiated suppression of key disease-driving biomarkers, namely exhaled nitric oxide and blood eosinophils. On the basis of those data, we have actually launched phase two programs in severe asthma and chronic rhinosinusitis with nasal polyps. We are, in the second half of this year, also initiating a program in chronic obstructive pulmonary disease. We'll be reading out our nasal polyps data in the second half of this year, and I'm very excited and imminently waiting for those data. We'll be about a year after that reading out our data in severe asthma.
A number of key milestones, a very sort of rich next couple of years for us, both from the standpoint of program development and hopefully from the standpoint of generating some very interesting data. We've got a great team who've been doing this for a while and know the space, and I'm very proud to be part of that team. As the result of an IPO executed towards the tail end of last year, we are well capitalized with sufficient funding to get through those two catalysts, the nasal polyps catalyst and the severe asthma catalyst, to initiate our COPD program and really to carry us through 2027. Now, when we think about differentiation, what are we talking about?
Those of you who follow this space know that there's a lot of sort of activity around TSLP right now, but we're going to look forward and we're going to look at where we think we might be able to compete if our trials are positive. That's going to be against marketed products, marketed products targeting TSLP like Tezspire and other drugs like Dupixent targeting the IL-4 receptor alpha and mepolizumab targeting IL-5. What you see when you look at our unique mechanism of action by targeting the TSLP receptor is that just from the standpoint of sort of a mini target product profile, I'll have said and I'll show you data underpinning the belief that we can potentially dose this drug either every 12 or 24 weeks.
We have done a lot of work to get our formulation such that we can deliver this in 2 milliliters or less, very compatible with autoinjector platforms and very patient-centric approaches to administering the drug. I think importantly, when you look at our data, our effects on exhaled nitric oxide, our effects on blood eosinophils, they are significantly better, certainly, than those that have been observed with Tezspire and certainly, I think, very competitive really across biologics in the space broadly written. Now, like Tezspire, because we're targeting TSLP, we do believe that we will not, and are certainly testing the hypothesis that we will not require any kind of biomarker limitation to determining our eligible patient populations. As I mentioned, we're developing Virecetug in a number of key indications. Our temporary first program is in chronic rhinosinusitis with nasal polyps.
Again, as I mentioned, that is due to read out in the second half of this year. We are on track to do that, having actually completed enrollment in that trial towards the tail end of last year. We are well underway in severe asthma as well, and we'll be delivering those data in the second half of 2026. We're actually at the point now where we're able to also initiate a long-term extension from that trial to develop longer-term data from these patients as well. Second half of 2026 for our severe asthma data, LTE initiation here shortly. I think importantly, initiation of a program in chronic obstructive pulmonary disease as well. Now, I've been using the words trials and program.
I think it's important to recognize that each of these studies that we are doing are designed, if positive, to potentially support a BLA submission as one of two potential registrational trials. Each have been sufficiently powered to detect a clinically relevant degree of efficacy. All are using really important endpoints and the kind of endpoints that both regulators and physicians, payers, and patients are going to look for. We will be delivering on this timeline really very important data for, we think, this molecule. I mentioned the team. We've got a great team. Many of the executives are here in the room with me. I think more importantly, we've got really a great set of functional leaders. We're a young company.
We're relatively small, but we've got people leading our teams and our functions that have been doing this for a long time and actually know this space and have really been head down and executing. Again, I'm very proud to be part of this group. I think TSLP is probably known to many of you as an important target in the space broadly construed in airways diseases and other immunology indications. It's a cytokine. It's an alarm that is expressed at the mucosal surface, predominantly at epithelial surfaces, so in the skin, the gut, and the lung. It's really sort of out there as almost a first line of defense cytokine so that if there's an environmental or infectious or other trigger, this cytokine can be expressed.
It can, as you see here on this slide, initiate a number of sort of key downstream inflammatory processes that actually drive the activity of a number of important cell types in terms of driving disease pathogenesis. What's been really interesting with TSLP, say, as opposed to IL-4, IL-13, IL-5, is that there appears to be a breadth of effect that is not just limited to the type 2 pathway, but also extends into type 1 immunology and even to some extent into fibrosis and potentially remodeling as well. It's likely this breadth of immunological effect that has allowed Tezspire to have its breadth of effect in populations. You see that manifested in the label. Again, by modulating very similar biology, we would expect to have a similar effect. We've focused very consciously on severe airways diseases as our initial approach for Upstream.
That's because the biology is de-risked. There's a molecule already out there being commercialized quite successfully. Again, we believe that we're differentiated. It is important to note that from just a life cycle standpoint, there may be other places that this molecule could be taken. Right now, we're sized, we're resourced to do what we're doing. We've chosen, again, indications where we think there's a significant degree of de-risking and also a significant commercial opportunity still. Our focus will be in respiratory initially, again, I think room to run. What are our data? We acquired this molecule actually from Astellas. Astellas discovered it in a collaboration using the Regeneron VelocImmune platform. It's a fully human IgG1. Astellas did beautiful preclinical work that actually gave a sign that this might actually be a very potent molecule.
On the basis of that, they took the drug into phase one, first in the single ascending dose trial in healthy volunteers. I'm going to show you the pharmacokinetics from that trial in a moment. There were some very nice early signals that this drug was well tolerated, that it had a very reproducible and consistent PK profile, that it was really highly available when administered subcutaneously. Importantly, nothing really from the standpoint of immunogenicity would really terminate the program or prevent it from going forward. I think the core observation that really has led to the excitement around this molecule is the fact that there is rapid, substantial, and sustained effect on those disease-related biomarkers that I mentioned. Those are important because in asthma, these biomarkers actually are reflective of disease activity. They're actually correlated with disease severity.
They're correlated with risk of key outcomes like asthma exacerbations. Also importantly, they're very responsive to therapy. You see these biomarkers being used over and over again in asthma biologics development programs, and they are highly translatable. We believe very firmly that they give us a sense of where we can take this molecule. Now, in the single ascending dose trial, as you can see, a range of doses were administered to healthy volunteers. Importantly, from a safety perspective, there was nothing that would prevent the molecule from moving forward. I've talked a lot about some of the pharmacological elements here, but importantly, there was dose proportionate PK.
When the data from the single ascending dose trial were actually subjected to modeling, what you could see here, and if we're just looking again over time and days on the horizontal axis and drug concentrations, model drug concentrations on the vertical axis, what you see is that even when those concentrations are plotted against a, at the time, very conservative level of efficacy, it became apparent that there was a potential that this drug could be dosed every 12 weeks simply on the basis of keeping drug concentrations above what at the time was thought to be the therapeutic threshold that was estimated on the basis of preclinical data. Now, what we've learned over time is that that therapeutic threshold, and if we just call it the EC90 for exhaled nitric oxide, is actually much, much, much lower for this molecule.
That has allowed us to actually move beyond Q12 week dosing as well. On the basis of these data, we then moved forward into a multiple ascending dose trial. Again, this was conducted in patients with asthma. It was randomized in terms of each sort of dose cohort. It was blinded. From the standpoint of this type of trial, methodologically, I think a very robust approach. You see that there were four sort of dose cohorts that were enrolled in this trial: 100 and 200 milligrams every four weeks, 300 milligrams every 12 weeks, and then a single very low dose of 25 milligrams administered once. Again, all these patients had asthma. They were required to have evidence of type 2 tone, as manifested by either elevated blood eosinophils or exhaled nitric oxide or both.
They were a stable population in which we first, again, importantly looked at safety, but also looked for early signs of pharmacodynamic effect that might potentially translate into some potential conclusions about efficacy. From a safety standpoint, both in this trial and from our experience thus far moving into phase two, the profile has been quite clean, very safe, very consistent with biologics in the space, and I think very reflective of what the Tezspire experience has taught us in terms of the safety of modulating TSLP signaling. When we looked at the pharmacokinetics from these patients with asthma and actually overlaid them, you see the dots here overlaid against those modeled curves that I showed you earlier, actually the pharmacokinetics were very reproducible. That was reassuring. I think most exciting was the fact that we saw very robust pharmacodynamics data.
Now, what do I mean when I say that? I'll draw your eye first to the left, which is the results of an assay in which we assess the extent to which Virecetug can occupy free TSLP receptors. What we see when comparing the different dose regimens in color versus the placebo line in black is that no matter what the dose, at two weeks, 100% of free TSLP receptors were occupied by Virecetug. A very rapid onset of this effect and one that continues even in the case of the single low dose for up to 12 weeks after that dose.
Now, in the cases of where we gave multiple doses, and you see those reflected by the arrows here in the bottom left, we see in fact that in a couple of these dosing regimens, that that effect on TSLP receptor occupancy persisted for actually at least 24 weeks. When we look at those data in the context of contemporaneous evaluations of blood eosinophils and exhaled nitric oxide in these same patients across the same dosing regimens, what you see is a very consistent in terms of magnitude of efficacy and duration of effect, very consistent associative effect on blood eosinophils and exhaled nitric oxide. Very exciting early pharmacodynamic data, again, suggesting that there was the potential to dose this drug at dosing intervals that have not, or at least at the time, were not on the table, I think, and data that were very exciting.
Now, we wanted to contextualize these a little bit. First, obviously, we were going to have to do dose selection for phase two, but we also kind of wanted to see how we would stand up against others out there in the field. Just very simply, we compared our data on the left at 12 weeks versus what has been reported from the Tezspire program at 12 weeks, looking in this case at exhaled nitric oxide, both change from baseline and absolute parts per billion on the top left and % change from baseline on the bottom right.
What we see is that whereas the Tezspire program has reported absolute changes of 17 parts per billion and % changes of around 25% at week 12, we saw a range of 28-47 parts per billion in the reduction in FeNO and about a 51-54% reduction in change when reading out from change in baseline. I think early signals that there was the potential for differential efficacy versus Tezspire, but we wanted to be a little bit more sophisticated than just doing sort of simple cross-trial comparisons. We subjected our data to pharmacokinetic, pharmacodynamic modeling, taking actually a very, very similar approach to that published with Tezspire.
What we saw was that in this case, again, just looking at exhaled nitric oxide, we saw that Tezspire had reported a potential maximal effect on exhaled nitric oxide of about a 28% reduction in FeNO. When we modeled our data, it yielded a potential Emax of 43.4%. I think even more impressively, when we looked at the concentration of drug that would be required either to achieve a 50% or 90% reduction in exhaled nitric oxide, you can see that those concentrations were 0.008 and 0.07 micrograms per mL respectively. Really about a 300-fold or greater lower effect in terms of the concentration of drug required to achieve an EC50 or an EC90. Really very compelling data from the standpoint of really reflecting the potency of this molecule.
When taking that into modeling to help us select dose for our phase two program in severe asthma, what we see when we then sort of model the data out over the course of a 48-week period, and we plot those in this case against now this sort of newly revealed EC90 for FeNO, again, much lower than that one microgram per mL that I showed you from the preclinical data, what we see is that we would predict that 100 milligrams administered every 12 weeks is going to keep the entire modeled population well above that EC90 for the entire 48-week period. That even administering 400 milligrams every 24 weeks, we are very, very likely to do the same with the exception of perhaps the last couple of days of that period.
Actually, our hypothesis going into our phase two trial in severe asthma is that these two dose regimens are not going to be different from each other. We'll see if that's true when we read out the data. On the basis of this modeling, both of these regimens were taken forward in severe asthma along with a lower dose of 100 milligrams q24 weeks and placebo. That trial is well underway. Again, we anticipate reading out the data in the second half of next year. As you can see, there are four arms. It's randomized placebo control, double-blinded, et cetera.
It's going to be looking at the regulatory endpoint of annualized asthma exacerbation rate as the primary, a number of very important secondaries there, with a sample size and an approach to power that puts us in a position to be able to detect a Dupixent or like Dupixent or better effect in the trial. We'll read that out in the second half of 2026. Our nasal polyps program, again, well underway. We've completed enrollment there, on track to read that out in the second half of this year. Again, really designed in a way to potentially provide very compelling data.
Now, we made the choice here only to take one dose forward versus placebo, largely to get to the point where we could take our sort of no-regret dose forward as quickly as possible to get data to really help, I think, reveal the potential of this molecule, knowing in part that there is such important biological linkage between nasal polyps and severe asthma that a positive outcome in nasal polyps could very much give us a strong read-through for probability of success in severe asthma. I do want to leave a few minutes for questions, but I just want to sort of contextualize this a little bit from the standpoint of the market opportunity because some of you may be asking, well, severe asthma, there are six biologics approved. We see Dupixent. We see Tezspire really doing quite well. Driving uptake, is there room for novel entrants here?
Our view is yes. Why is that our view? The first is that the market dynamics have been such that over time, there really is a substantial degree of underpenetration of biologics into these eligible patient populations. What that has sort of done is provide an environment where, first of all, there is opportunity for existing entrants to continue to acquire market share. Also, very interestingly, there has been the opportunity for new entrants, particularly if they are differentiated in some way, to come in and actually gain substantial share, not by eroding the share of others, but by actually creating a new opportunity for themselves. What that has sort of led to is a substantial market opportunity. Here, we are using Data Monitor and suggesting that the biologics market in severe asthma is ripe for growth.
It's going to continue to grow at about 6% annually, at least through 2032, and may end up at sort of annual sales of $12 billion or more. That's, I think, a real significant opportunity. Obviously, a lot of that is centered in Japan, EU, and US with $7.5 billion in 2023 alone. Again, a lot of opportunity there. We've been really impressed by the Tezspire launch. It's a very good molecule. They've done a great job with it. I think because of its relative efficacy versus others and because of the fact that it's not limited by biomarker, it's had a very broad degree of penetration thus far. That accounts for, you see here, sort of the green swath continuing to grow over time.
Again, courtesy of Data Monitor, just showing you sort of the dynamics that I referred to earlier where new entrants, particularly if they're differentiated on efficacy or other domains, taking substantial share. We anticipate that that will continue to be the case in severe asthma. Although it's very, very early days for biologics and COPD, the dynamics are very similar here in terms of prescriber, in terms of how these drugs are used, stepping through inhaled therapies, and many other dynamics that we think may very much create a similar opportunity for novel entrants in COPD as well. Now, it's important to us to be in touch with our investigators. It's important to be in touch with people who may one day be our customers in the form of payers or physicians or patients.
We actually spend a lot of time looking externally, talking to people, doing market research, boots on the ground at major conferences, getting feedback in real time about data. What we've learned is that there's a lot of support for Virecetug, at least based on a Tezspire-like efficacy profile with a dosing interval of either q12 or q24 weeks. What we see is a high degree of patient interest. People really want convenience. Four times a year, two times a year would be much more convenient than every two or four or eight weeks. We see physicians, I think, really reflecting that in their decision-making. They want a breadth of opportunity in terms of biomarker restriction. They ideally want differentiation on efficacy, but they also very much want what's convenient for their patients.
From a standpoint of mechanism of action, dosing interval across payers, physicians, and patients, so far, we've seen a lot of resonance of this profile. Now, we need to read out the trials. It's a long way before we get to the market, if we ever get there, but really very good early signals for what this profile could bring. Just the last word on COPD, the epidemiology, I think, is such that this disease is more prevalent than severe asthma. The penetration of biologics is only beginning now with the approval of Dupixent in COPD. There is significant unmet clinical need.
I think that's to some extent reflected by all the development programs for biologics in COPD, but also by the fact that there are really significant effects seen in the clinical programs with regard to exacerbation reduction and other important clinical outcomes as well. We're very excited. As a pulmonary physician, I'm really excited to see this as a sort of a new opportunity in terms of providing efficacious therapies for patients. We hope to be part of that one day. That'll be to help patients, but it'll also be to take advantage, we hope, of a very significant commercial opportunity as well. Let me stop there. I'll just remind you of where we started. We're, again, really excited about the molecule, the company, the program. We're working hard to deliver on time. We believe that we have the potential to be differentiated.
I think, importantly, we're well ahead of many others out there trying to do the same thing. We're going to do our best to move this forward and be successful. Thank you.
Maybe a couple of questions. The first one is we just saw the Tezspire phase three data, the Waypoint.
Waypoint.
Waypoint. At Quad AI. The data looked, in many, at least on par with Dupixent, in some capacity, even on some of the scores, even better. They're obviously moving ahead. What are you expecting to see from your study? It's obviously smaller in the second half. And then the COPD study, not to get ahead of it, are you thinking about doing 150? What's the threshold that you're going to be using on baseline levels? Sure.
For the first question of what we would expect to see in NP, I think we're, again, really reassured that TSLP modulation, I mean, we already saw this in the secondary analysis of the asthma data that they did, but to see it really read out in a prospective placebo-controlled trial, I think, was quite nice. I think we would concur with you that the data are roughly on par with those of Dupixent, maybe slightly better. There are some differences in study design, baseline population characteristics, et cetera, that are always a bit fraught when you're trying to do cross-trial comparisons, but validation of the pathway in NP. I think that then allows us to go back to sort of our core set of fundamentals, which are how are we differentiated potentially from Tezspire. It's on potency.
That potency is reflected by the potential to dose this drug far less frequently and potentially by room to improve on efficacy as well. I do not want to get too far out ahead of ourselves on the efficacy side. We will have to see. I think we feel very good. We know, again, from our market research that a TESI-like efficacy profile with q12 or q24 week dosing is a differentiated profile in the eyes of the market. More to come there and not that far off in the distance. I think in terms of COPD, we, again, were really reassured and learned a lot from the TESI COPD data that were reported at ATS last year. That trial was not designed to be, I think, definitive. It was a little bit more of a proof of concept study.
It really gave us some very powerful data, I think, on the association between type 2-ishness as reflected in eosinophil counts and efficacy. I would have gone into that, I think, thinking that that relationship is somewhat linear. I think we kind of came out of those data thinking that it's somewhat linear. We're also not naive to think that there's something magic about 150 or 300 or 75, that it really is a continuum. We have been putting a lot of thought with regard to our COPD program about where to draw that line and how to design a trial that is appropriately de-risked and can be appropriately contextualized when it reads out, but also gives us room to explore some of these open questions.
We will, I think, look at 150 as a potential sort of primary and up as a primary analysis population with the potential to really deeply explore eosinophil counts less than that and do the kind of dose ranging that you would expect so that when this trial does read out, it gives us really good data in hand to design a phase three if positive. The question that we get frequently is understanding the PK to PD function of just given the receptor versus ligand binding. Can you discuss that a little bit more? Sure. I think maybe the best way to contextualize PK PD is to look at our data and look at our durability and compare that with the approach of targeting the ligand and also adding an Fc engineering approach like YTE mutation to give an extended pharmacokinetic profile.
What we have seen, I think, in general across the board, and there are many who are taking this approach targeting the ligand and trying to extend half-life, is that in general, most of those molecules do not have the degree, in fact, none of them have the degree of potency that we do. In fact, they are all very similar, I think, both from a preclinical and where we have seen it early clinical data standpoint to Tezspire. What the YTE mutations do do is extend the half-life, maybe three- or four-fold. If you are a company making decisions, you can make a decision about how far you then want to push the dosing interval on the basis of that extended pharmacokinetics. You can look to a number of companies to see what choices they have made there.
It's important, we think, to keep that relationship between half-life and dosing interval in these cases pretty tight. If you push that, excuse me, if you push that too far, you could find yourself in a position where you start to actually have lost either a pharmacodynamic or clinical effect towards the tail end of that dosing interval. That, I think, is maybe starting to reflect itself a little bit in some of the data that we're seeing from some of the YTE mutated antibodies in this space. Again, we need to generate our data, but at least on the basis of our preclinical and sort of MAD data, there does not appear to be a loss of durable efficacy or pharmacodynamic effect over the 24-week period. How that plays out clinically and whether or not that makes a difference, I think TBD.
We do know that it's really important for these patients to maintain symptom control, to keep exacerbations from happening, and to do that for the full duration of the interval so that patients don't experience loss of control, have to use more rescue medications, take time off of work, school, et cetera. Several companies are testing now bispecific or trispecific, essentially, and IL-4/13 or 13 TSLP, a combination of those. TSLP is already upstream of 4/13. It's upstream of 5 as well. What's the benefit of hitting both TSLP and 4/13 at the same time? Yeah. I think the best way to answer that question right now is with the data that we have available to us.
I think what we would say is, if you look methodologically, for example, at a very similar MAD study approach with patients with asthma, high T2 tone, what we've seen, for example, with Sanofi's Linsecamig is an effect, and that's a multi-VHH construct targeting both TSLP and IL-13. We've seen a very robust effect, actually, on exhaled nitric oxide, but an effect that is essentially equivalent to ours or maybe even slightly less than ours. I think that's one data point maybe to say, and of course, they're doing a larger program as are we, and we need more data. We think that that's one data point that suggests that if you have really good monoblockade of an upstream node like TSLP, there may not be actually anything that can be added to that. There are a lot more bispecifics out there.
You're hearing about co-formulation and other approaches. We're going to get more data on this. That's one data point. I think the other is that there was an interesting paper that was published in The New England where Dupixent was administered contemporaneously with itepekimab, the anti-IL-33, so another sort of key node, IL-4 receptor alpha, plus an alarmin-targeted antibody. There, you didn't really see any incremental efficacy that was achieved through that approach versus that achieved with Dupixent alone. Our view at this point, based on the data available, is that there may not actually be a strong rationale for multi-specifics and similar approaches, multi-targeted approaches in airways diseases, but it's early days.
I know we're over time. Is there specific data that you know of testing Tezspire in a Dupixent failure in asthma and vice versa to see whether it makes sense to sequence them as opposed to going concomitantly?
Yeah. I don't know of any data at this point. I mean, it is likely true in the Tezspire program that there were patients who were biologics experienced. Now, patients stopped biologics for all kinds of reasons, not just because they didn't work. I don't think we can call, and that happens, I think, across the board in these programs. You can't really call those failure populations. No, I'm not aware of any data at this point. There may be some that are out there in poster form, but it is an important question, actually, and one that I think we'll see somebody do in life cycle at some point along the way.
That was terrific, Rand. Thanks so much for coming. We appreciate it.
All right. Thank you. Appreciate the opportunity.