Upstream Bio Aktie

Good morning, and thank you for joining us today. My name is Elizabeth Webster, and I'm on the biotech equity research team here at Goldman Sachs. And today with us, we have Rand Sutherland, the CEO of Upstream Bio.

And Rand, to start, can you introduce Upstream, your lead assets and how you see the company positioned today and where you're most focused as we head into the second half of the year?

Sure. I'd be happy to. And Elizabeth, thank you for having us. It's a real privilege to be able to share the Upstream Bio story here today. So Upstream Bio is a clinical stage company. We're developing an asset called verekitug. Verekitug is a monoclonal antibody. It targets the receptor for TSLP. So we are active in a space that is, I think, getting a lot of interest from drug developers right now, but we do so with an approach that is actually unique in that space and that we target the receptor by virtue of targeting the receptor.

We have a very potent molecule. We can spend that potency in 2 ways. One is efficacy and the other is dosing interval. And we are now emerging from Phase II studies in 2 major indications, severe asthma and chronic rhinosinusitis with polyps with an ambition to deliver efficacy that is best-in-class to do so with convenient quarterly dosing, to provide that in a very broad population, irrespective of biomarker status, and to be able to do it with clean safety and importantly, for launch with self-administration at home via an auto-injector. So that's a very potentially competitive [ TPP ] for what we hope to deliver here. And we have these aspirations not based on sort of ideas, but on actual data from hundreds of patients coming out of Phase II, and I'm sure we'll get into those as we go through here.

Great. And before going into the individual programs, maybe just speak a little bit more about the choice to block the receptor for verekitug versus other approach targeting the ligand and mechanistically what that means for the clinical profile?

Sure. So the TSLP ligand receptor system [Technical Difficulty] repair, the TSLP receptor is a heterodimer [Technical Difficulty] verekitug is that by virtue of targeting the receptor, we can actually completely shut down signaling through that TSLP pathway. We very early on after administering verekitug achieve 100% free receptor occupancy. And we've shown in preclinical studies and now we've early clinical and now mid-stage clinical development that, that is associated with efficacy that meets or exceeds that of TEZSPIRE and in fact, all other biologics in the space does so with 4x per year dosing.

And we believe that in large part, this is due to the fact that the receptor is expressed at quite low levels versus the ligand. And so even many half-lives out in a fully human IgG1 that is not engineered at all for half-life extension, we have enough drug around to continue to have effect at quarterly dosing. So that's a very distinct approach from the competition, which in every other case is targeting the ligand. The circulating ligand is expressed at a much higher level than the receptor. And what's being done there rather than modifying the potency of the molecule is actually employing half-life extension. So there are different approaches trying to provide efficacy at extended dosing in this space. Ours is unique, and we do believe on the basis of our data that it is also potentially quite differentiated.

Great. We can get started with asthma maybe first. And earlier this year, you presented Phase II VALIANT study data in the severe population. Just to level set, can you kind of recap the highlights from that data?

Sure. So as you mentioned, VALIANT was our second Phase II placebo-controlled trial in a major indication, in this case, severe asthma. And the intent of the VALIANT trial was really to help inform the pharmacology, further understand the pharmacology of the molecule and to inform our approach to Phase III. And VALIANT did a beautiful job of doing that. So just at a high level, this was a study in around 480 patients in which we tested 3 different dose regimens versus placebo, 100 milligrams every 12 weeks, 400 milligrams every 24 weeks and then as a sort of a low-dose regimen, 100 milligrams every 24 weeks as well.

And so we went into this study with the hypothesis that it was going to be really important to deliver efficacy that again, met or exceeded that of best-in-class and did so with extended dosing. And we also went in with the belief that the most important thing to deliver here is efficacy. We know from a lot of market research from a lot of one-on-one with physicians and patients and payers that efficacy is king. Convenience is nice to have. It may actually result in improved compliance and drive better outcomes over time, but nobody is willing to make a trade-off of efficacy just to get through extended dosing.

And so we went in trying to understand what was the best way to optimize the characteristics of verekitug. And what we found was with the highest dose regimen at 100 milligrams every 12 weeks that we were able to deliver a significant and clinically meaningful reduction in the annualized asthma exacerbation rate of 56%. That was accompanied by clinically significant improvements in lung function and symptoms asthma control and also by important reductions in disease-associated biomarkers like exhaled nitric oxide.

Now we did also see degrees of efficacy with the other dosing regimens, but they did not meet our test of highest efficacy and durable dosing over a very convenient dosing period. And so for that reason, we've really now focused on quarterly dosing as the approach that we're going to take going forward in the program. And we very much, again, want to achieve that convenient quarterly dosing and pair it with really top-of-class efficacy. So that's our ambition coming out of Phase II. And I would say that this is based not just on the data from the VALIANT trial in severe asthma, but also from [Technical Difficulty] data in the VIBRANT trial with CRSwNP, in which we also delivered really outstanding efficacy across all endpoints at quarterly dosing with that 100 milligrams Q12 as well.

And maybe just frame the impact of quarterly dosing for patients and clinicians and kind of any market research you've done about how that profile is being viewed by the clinical community?

Sure. So I think just to level set, it's important to understand that biologics currently available with the exception of Depemokimab are all dosed every 2 or 4 weeks. Those are also the most efficacious of the molecules available. Of course, they differ in which patients could get them, which efficacy according to which parameters. And I make these points because it's a complex landscape. And what physicians, again, and patients and payers all want before quarterly dosing or twice yearly dosing is great efficacy.

But when you then do market research and you hold efficacy, let's just say, at a level equal to TEZSPIRE or potentially better than TEZSPIRE and you start to extend the dosing interval, that actually becomes a very competitive profile. It becomes one, at least in market research settings that can compete very effectively for new prescription and which may, in cases where a switch is necessary, also be a competitive profile there as well. So extended dosing is nice to have, but it has to be paired with great efficacy. I keep making this point because we do think that there are challenges in this space, and you really have to be able to deliver both to have a competitive profile.

And then just remind us of your timelines for moving to Phase III and your interactions with the FDA?

So we have been prosecuting both of these clinical programs essentially contemporaneously all along. So we had our nasal polyps data in the fall of last year. Of course, earlier this year, the severe asthma data. We've taken the time to very carefully model and understand those data in aggregate. So we have 500-plus patients worth of data. We've been looking at a number of things, including overall efficacy. We've been looking at dose response, and I know we'll talk about our plans for dose going forward in Phase III. We've been very careful about understanding the safety profile of the molecule. And we've now taken all of those data and actually contemporaneously are looking to engage with the FDA on the path to Phase III in both indications. We expect to be done with those interactions by the end of Q3 of this year and remain on track to dose our first patients in the Phase III programs in both indications simultaneously in the first quarter of next year.

One of the things, and maybe we'll get to the commercial space a little bit, but one of the key attributes for access and formulary, of course, is having multiple indications. And so for us to be able to potentially launch with 2 indications at the same time, we think could be an advantage as well. And so we've been very careful to try to leverage the findings from each program to support the other, both from the standpoint of safety and efficacy and one can move forward relatively again at the same time so that we could potentially launch with the label of both indications.

Got it. And maybe just touching on that commercial front. When we think about kind of the reimbursement landscape and payer dynamics, how do you see that kind of playing out with a longer-acting agents assuming efficacy at par with TEZSPIRE?

So this is all very forward-looking, right, because we're a few years away from this. Maybe just to step back and comment on the space broadly and what we've learned over the past decade or so that biologics have been around. It's -- what's interesting today, even though there are now 7 biologics approved in severe asthma, they're all unique in some way. They target different aspects of the type 2 inflammatory process. They have been shown to be efficacious in specific subgroups. They have different degrees of efficacy.

And the value of that in terms of -- sort of physician decision-making is that you can actually look at a patient and you can ask, all right, based on the clinical status, the inflammatory status, what's the right drug for the right patient at the right time. And so the market has very much supported having this optionality because of the biology of the disease and how we try to treat individual patients. So it's kind of a heterogeneous landscape, but it's one in which there is enough white space occupancy by all these entrants that they can -- everybody, for the most part, has been successful from the standpoint of commercialization.

What happens when new [Technical Difficulty] white space at others [Technical Difficulty]. So you really, again, want to deliver something that's unique either from the standpoint of efficacy, eligible patient population, convenience, et cetera. And when we have seen that happen over time, particularly with Dupixent and then TEZSPIRE, these are differentiated agents, and they have very successful launches. They are able, in the case of Dupixent to extend into many, many indications. And they gain share actually not necessarily by eroding the share of others, but by driving the overall penetration. And yet despite all of this, penetration is still around 25%, meaning that there's 75% of patients who don't have access to these drugs right now.

So we believe that you have to come in, you have to be differentiated. In our case, the ambition is to be differentiated on efficacy to have that same broad label that Tezepelumab, TEZSPIRE does and then to deliver this convenient dosing, which may be actually associated potentially with greater compliance, greater long-term outcomes. And I think then gives when it comes time to compete for access and in the market, a very differentiated profile versus the others. So we think that all of these things matter. It's going to be really key, I think, for formulary access to be differentiated in these ways. And then other things like pricing and sort of [ GTN ] and all these other things start to matter. But efficacy, a number of indications, clear differentiation. If you start with those, you start on the front foot.

Great. That's super helpful context. Just want to touch on CRS with nasal polyps. Maybe just frame kind of what you're looking, what the profile you're looking to achieve is in Phase III and I'm just reminding us of kind of what you've shown to date in that indication.

Yes. So CRS with NP, it's not a disease that gets as much attention as severe asthma. It's certainly less prevalent, but it's still there's substantial unmet need and substantial commercial opportunity associated with it. So it's essentially a form of inflammatory sinusitis. Patients get thickening of the lining of the sinuses and then these outgrowth of tissue called nasal polyps. Those basically obstruct the sinus, they make it hard to breathe [indiscernible] sleep apnea, difficulty with taste [indiscernible]. Historically, treatment has been surgery and steroids, and it's really only with the advent recently of efficacious biologics that there's been sort of a new potential standard of care that's been brought to bear here.

So this is a disease that is highly type 2 driven. And so we know if you can modulate this biology effectively, you can have significant clinical impact. And that's, in fact, exactly what we showed in our Phase II trial, the VIBRANT study. Again, placebo-controlled 100 milligrams Q12 weeks of verekitug over a 24-week study. In that case, we showed an almost 2-point reduction in the endoscopic nasal polyp score. We showed both clinically and statistically significant improvements in all secondary endpoints and most importantly, showed a substantial reduction and the need for surgery and/or oral corticosteroid or systemic corticosteroid rescue.

So that was a big win for us. It really showed the fact that verekitug is very successful at modulating type 2 biology that translates quite meaningfully to clinical endpoints. And we are very optimistic that we are going to be able to show something quite similar in Phase III. So we are moving forward quickly there. Of course, it's may be the purest of the type 2 inflammatory diseases of the 3 that we're studying, but we know that there's clear read-through, and we've actually shown in asthma subgroup data from our nasal polyps study that there is efficacy on both diseases when they are comorbid.

And again, we believe that there's, I think, a very derisked program here that's going to go into Phase III, see what the data show at the end of the day. But this could potentially be a best-in-class medicine for that disease, again, with convenient quarterly dosing administered at home or potentially in office. We actually have done the work and the investment as part of our program all along to have both an auto-injector and a prefilled syringe. And I think that's important to recognize as we think about potential in-office administration and sort of an ENT or allergist setting versus at home, maybe more consistent with how pulmonologists practice.

Great. And then can you kind of speak to the translation you expect from Phase II to Phase IIIs and how you're planning to manage placebo responses in the Phase III?

Yes. So I think it's a bit of a different answer in CRSwNP versus severe asthma, partly because of the nature of the Phase II studies, and I think the robustness of the data from the CRSwNP study versus the more sort of, again, sort of pharmacology informing approach that we took in Phase II and severe asthma.

So again, forward-looking statement, but I think that there's a high degree of translatability of the data that we saw in Phase II in CRSwNP forward to the Phase III. We would look to recapitulate the same magnitude of efficacy, do it in a very similar patient population. And again, try to across the board, show impact on endoscopic nasal polyps score, nasal congestion score. Actually, we looked at CT indices of sinus inflammation. There are a lot of sort of symptom and quality of life indicators. And then again, this important clinical endpoint of need for surgery or rescue steroids. So that will be the approach, and I think a high degree of translatability there.

I think as we look at how the Phase II was designed, recall that the statistical power in that study was really focused on the primary endpoint of reduction in asthmatic exacerbations over the course of a year or annualized. And so we feel that those data are quite translatable. All of the secondaries, all of the subgroups were more exploratory in nature. They're there to help understand how the drug might perform in Phase III. And so what you see, and this is true really across many of the biologics programs in severe asthma is that while the Phase II is helpful in informing the design of Phase III, some of the statistical import of the subgroup analyses are really quite fragile and not as robust.

So I would not predict to say that we will see one thing or the other as directed by Phase II and Phase III in severe asthma. But what I will say is that we are very clear about what the things that we need to do are coming out of Phase II. So the first is we've learned from our Phase II data that there is clear evidence of exposure response. And so for that reason, and I think we'll get to this in a minute, we're potentially going to take a higher dose forward in Phase III to really drive the magnitude of efficacy, both in severe asthma and CRSwNP.

And we're also going to look very carefully at what we can do in Phase III to make sure that we have adequate background exacerbation rates in the placebo and treated arms such that we don't run into a situation similar to what we ran into in our Phase II, where the exacerbation rate was so low, for example, in the low EOs group in our Phase II that there just was no ability to break through that and show efficacy. And you can do that by changing exacerbation requirements from the inclusion criteria standpoint. You can do it by looking at sort of how standard of care therapy is applied. You can look at it and modify it by where you go in the world. And so there are a lot of approaches that companies take going from Phase II to Phase III to really help enrich the signal so that you can then break through that with an [ efficacious ] therapeutic.

Great. And you mentioned the dose work that you've done, expand on that and how to think of the PK and the PD of the molecule?

Sure. So again, we're fortunate and I think unique amongst the competitive landscape to have now hundreds of patients of data coming out of Phase II and going into Phase III. Again, the antibody is a fully human IgG1. It was actually a product of Regeneron's VelocImmune platform. So it has a fully human IgG1 half-life of around 20 days. So no half-life extension there. The PK, I think, is quite well understood. It's really, again, the potency that drives the pharmacodynamic effect with regard to biomarkers and the clinical efficacy that we've seen in our clinical trials.

So we, I think, understand this very well. And what we've learned from these hundreds of patients' worth of data is that when you look at the relationship, so if you just take, for example, the highest dose regimen of 100 milligrams Q12 because you're administering this to a population of humans and humans are variable, you're going to have some patients who get higher exposure and some patients who get lower exposure, even holding the dose regimen constant. And when we take the overall population and divide it into third, and we just compare very simply the highest exposure tertile to the lowest exposure tertile, what we see is that there's a significant additional degree of efficacy.

When I say significant, not statistically, but clinically with regard to the magnitude in our asthma trial of FEV1 response and in our CRSwNP trial of nasal congestion score response. What we see is as you push the exposure, you push the efficacy. And so our approach to the upcoming negotiations with the FDA is to share all of this work with them. We've seen this not just in the kind of sort of qualitative analyses that I've discussed with you, but really in very precise quantitative modeling from a PK and PD standpoint and understand that by pushing the dose potentially as high as 400 milligrams every 12 weeks, we can get that potentially additional efficacy and very clearly maintain patients above not only the concentration levels that are needed to meet that sort of highest tertile level that we observed in the Phase IIs, but also well above the EC90 for exhaled nitric oxide in the population.

So we can do that 400 milligrams in a simple 2 cc administration because we have a very formulated concentration -- a very concentrated formulation. And again, would do that with a PFS or an auto-injector at launch. So we'll know very shortly if the FDA agrees with us with regard to this. Again, we don't think that this is too speculative because it's based on, again, very robust data sets, very high-quality modeling. And the ambition, again, is to push the efficacy as high as we can and deliver convenient dosing.

And in your dosing regimens for Phase II and potentially Phase III, just kind of remind us whether there is increased dosing in the induction period. And what that regimen is?

Yes. So we're very fortunate that induction is not required here. We had very robust in fact 100% occupancy of TSOP receptors within 2 weeks, actually sooner. And so you do not need to load or do any kind of induction to get efficacy. And we've pretty clearly seen that. There is some element of dose response even at the first time point of measurement in our Phase II trials. And so for that reason, again, we're going with potentially a higher dose here. But yes, we do not need to induce. And so that's actually from the standpoint of the overall convenience and I think potential performance in the commercial space quite potentially differentiating as well.

Switching over to COPD. You're running a Phase II placebo-controlled study and the moderate severe patients with quarterly and then I think biannual dosing. Can you just talk about your confidence in the TSLP mechanism in this indication and differentiation for verekitug here?

So we were actually really excited by the data that Amgen AZ produced with tezepelumab in COPD because I think just very simply, they showed great efficacy in that trial. And that, of course, was paired with efficacy that had been observed with Dupixent and also even with IL-5 like Nucala in COPD as well. I think if you just step back to the biology of the inflammation in COPD, we touched on this a little bit. It's probably the most heterogeneous of the 3 indications that we're targeting. There's clear type 2 driver inflammation in this disease. There's also a lot of type 1 inflammation as well. We know that TSLP has an advantage in working across both of those pathways of inflammation.

And we believe that actually this maybe of all the diseases is the place where the potency profile of the molecule could be the most translatable. Again, we'll see what happens with our data. We initiated, as you mentioned, the Phase II trial, again, placebo-controlled, testing multiple dose regimens in COPD. And that study has actually enrolled quite well as we got the data from our Phase II studies in CRSwNP and severe asthma and as we learn more about this dose response and as we decided from a strategic standpoint to potentially take a higher dose regimen forward in CRSwNP and severe asthma, we've elected now to truncate that final bit of enrollment in the COPD study, use the patients that have enrolled -- have been enrolled and the dose regimens that are being studied to really help us understand more about the potency of the molecule in this disease, understand the translatability of that potency to efficacy signals, but also not necessarily wait for those results to initiate a Phase III trial in COPD, again, contingent on dose regimen sort of selection and alignment with the FDA.

So that actually is a good thing for us because it allows us to get a lot of information out of this -- out of the Phase II program in COPD, but it doesn't require us necessarily to gate initiation of Phase III in COPD on that given how much we've learned from the program. So we've been very careful about trying to be able to leverage the maximum amount of information from the program at large as we move forward in these various diseases. And we see an exciting opportunity here. We're going to learn more about the data as they start to emerge. And we expect that in the second half of next year, 2027, we will have a fairly robust understanding of the performance of verekitug in COPD from that program, and again, are potentially prepared to move forward quickly in Phase III as well.

Okay. And do you anticipate ultimately to have both quarterly and biannual on the label? And then just how are you approaching that kind of alpha spend that you mentioned around potency in COPD evaluating both of those kind of dosing frequencies?

Yes. I think it would be surprising to see in COPD greater or more durable efficacy really in any of the dose regimens versus, say, CRSwNP and asthma, again, just rank ordering that based on the degree of type 2 inflammation. So we do believe that by taking a high-dose regimen forward with quarterly dosing, we can deliver efficacy in COPD. We need Phase II data to help reinforce that. But we are not in any of the indications contemplating having multiple doses or dose regimen, single dose regimen, again, we need to maximize efficacy, we do not believe that there is any -- and this is not just a belief, but again, on the basis of a lot of market research and data, we do not believe that the difference between Q12 and Q24, Q26-week dosing is substantial when it comes to any trade-offs that might be required.

And it is important to look at sort of what is out there from the standpoint of the data. If you look at our data, while we did deliver actually a reasonably significant reduction at Q24 weeks in asthma exacerbations. When we look overall at the data, those data were not as durable. We started to see loss of symptom control, lung function control with Q6-month dosing, that actually has been replicated in the clinical programs of the long-acting IL-5. There are some early clinical data from some of the long-acting TSLP ligand targeting antibodies that use half-life extension that raise questions about the durability.

So we do not -- nobody wants to take the risk with us and patients and physicians I'm talking about here of having a loss of efficacy just to get to 6 months. So we believe that quarterly dosing is quite competitive. It is incredibly valuable when paired with optimal efficacy, and that's what we're going for. We're putting our nickel down, and we believe that that's the best profile. And we believe that it actually may be the best profile that any of the competitive landscape can potentially deliver.

And speaking of the competitive landscape, what are your thoughts on some of the either co-formulated IL-13 TSLP therapies or the IL-13 class in general here? And just is there any efficacy that's kind of left on the table, so to speak, with a single target?

Yes. I think the short answer is that it's hard to know because we haven't really seen much in the way of data from anybody yet. I think the soonest that we'll get a read on this is probably from Sanofi's bispecific program, lunsekimig in severe asthma. They have data that we are all expecting to see here in the second half of the year and which at top line, at least have been reported to be positive. They did Phase I multiple ascending dose trial in asthma, very similar to ours and actually showed very similar degrees of reduction of exhaled nitric oxide versus ours. So how that translates to differential efficacy, we'll see. But that -- rather than speculating, I think once we have those data, we'll have the answer.

I would note that there are other data sets of TSLP IL-13 combinations in type 2 inflammatory diseases that haven't actually shown additive effects. Those data are mostly from atopic dermatitis programs. And there was even the study that Sanofi Regeneron published a few years ago, combining dupilumab with an anti-alarm and the [indiscernible] IL-33, which did not demonstrate additive efficacy in severe asthma over that achieved with Dupixent. So it remains to be seen whether if you're targeting TSLP, which is upstream of everything else, and you're doing it really, really well, I think there is an open question around whether or not you're getting any additive efficacy by targeting things downstream.

So we'll see. There are Pfizer's trispecific data in atopic dermatitis, which may have demonstrated at least from [indiscernible] standpoint, some differential efficacy. But I think we're learning more about this, and there are data sort of Pfizer's trispecific on the positive side, a lot of other data not demonstrating differential efficacy. And I think lunsekimig will teach us more here soon. So -- but having said that, what is very clear is that verekitug delivers efficacy as good as TEZSPIRE or better in 2 type 2 indications with quarterly dosing. The only way we could have done that is via potency. And again, we have a high degree of belief that, that will translate with appropriate design and appropriate dose selection into Phase III.

And in the last few minutes here, remind us of your cash position and runway and how you approach capital allocation across your pipeline?

Sure. So as of last quarter, we had almost $300 million, that continues to fund us through 2027. And what that funds is actually really sort of a max plan for everything that is in our ambition. So that's sort of the initiation of our Phase III programs to continue in severe asthma and CRSwNP. It's the continuation of our Phase II program.

And as I mentioned previously, we are very fortunate to have a formulation that is very close to, if not -- I mean, we still to do [ PPQ ] and everything, but the commercialized formulation. We are making heavy investments in device, as I mentioned, and we believe that these are all critical for a successful launch. I would note that our understanding that also puts us in a very differentiated position versus much of the competition. And so we will continue to fund all of that as we move forward. And in terms of -- sort of approaches to raising additional capital, we, of course, have a lot of tools available to us, the equity markets. We are constantly talking with potential partners about approaches to non-dilutive funding, and we'll be very thoughtful and careful there as...

And to close out, what do you think about the -- are there any aspects of the story here that you think are underappreciated at the moment by investors?

I think it's -- we feel that there's a dislocation between the value that's being reflected in the stock market right now and the value of the company. This asset has been extremely well studied. It is -- derisked is always a fraught word because you never know until you know. But again, we are unique amongst the competitive landscape and that we have many hundreds of patients' worth of data. We understand the pharmacology of this molecule. We, I think, have a very rational and reasonable approach to the FDA interactions that are upcoming here.

And I think with -- the other point is that we've really executed quite well over the history of the company. And so we are in a position to have a potentially quite differentiated molecule not that far from now. And back to the market dynamics, if we can deliver that, verekitug will be a very differentiated molecule. It will potentially transform the care of patients who don't have access now and are not being treated with biologics. And we're very optimistic and excited about what's to come next.

I do think there's a lot of competitive noise right now. There are a lot of things going on. There are a lot of these open questions, and they need to be answered. And our approach has been we're going to answer them. We're going to provide the data. We're going to make it public. We're going to share them, and we're going to give people a reason to believe. So we're extremely excited. We have a lot of work in front of us, but we do believe in the potential of verekitug to be a transformative medicine in this space, and we really are working hard to deliver that.

Well, with that, thank you so much, Rand, for joining us today.

Thank you. We appreciate it.

Thank you for standing by, and welcome to the Upstream Bio Phase II VIBRANT Top-line Results Conference Call. [Operator Instructions] As a reminder, this call is being recorded.

I would now like to introduce your host for today's conference, Meggan Buckwell, Director of Corporate Communications and Investor Relations at Upstream Bio. You may begin.

Good morning, and thank you for joining us today. Before we begin our formal comments, let me remind you that during today's webcast, we will be making forward-looking statements that represent the company's intentions, expectations or beliefs concerning future events. These statements represent our views as of this date and should not be relied upon as representing our views as of any subsequent date in the future.

Additionally, please note that this presentation includes comparisons of verekitug against existing treatments and product candidates in development based on third-party published data. Head-to-head clinical studies have not been conducted between verekitug and these products and differences exist between trial designs and patient characteristics. Caution should be exercised when comparing across studies.

With me today are Upstream Bio's CEO, Dr. Rand Sutherland; and Upstream Bio's Chief Medical Officer and Head of R&D, Dr. Aaron Deykin. Looking at our agenda today, Rand will begin the call with an overview of the results and introduction to Upstream Bio and our plans for our lead asset, Verekitug. Aaron will then review the Phase II VIBRANT clinical study top line results in detail, after which Rand will conclude the call, and management will take questions.

I would now like to turn the call over to Rand Sutherland.

Thank you, Meggan, and thank you all for joining us today. We are thrilled to share the top-line data from the Phase II placebo-controlled randomized VIBRANT trial of Verekitug in chronic rhinosinusitis with nasal polyps or CRSwNP. As Aaron will share in detail in a few minutes, verekitug administered just once every 12 weeks, had clinically and statistically significant effect at the end of this 24-week study on the primary endpoint of Endoscopic Nasal Polyp Score as well as key secondary endpoints, including the Nasal Congestion Score.

Remarkably, this trial also demonstrated a significant impact of verekitug on the need for steroids or surgery in study participants. Verekitug was also generally well tolerated with no serious adverse events reported consistent with previous studies. These trial results further extend the consistent body of preclinical and early clinical data from our development program which together suggest the potential for verekitug to deliver meaningful clinical benefit at a significantly reduced dosing interval versus other biologics. These are the first placebo-controlled data for an extended dosing interval agent in the TSLP pathway, supporting our intent to develop verekitug in this and other indications, including severe asthma.

I'd like to put the verekitug data in context of the current landscape of approved or investigational treatments for CRSwNP with a focus on TSLP. This comparison is for illustrative purposes only since head-to-head studies with verekitug have not been performed and study methodologies may differ. With these caveats, verekitug administered every 12 weeks, equivalent to 4 times per year, demonstrated improvements in absolute and placebo-corrected endoscopic NP asset 24 weeks that were generally consistent with those seen with Tezepelumab, which requires administration every 4 weeks equivalent to 13x per year to achieve this effect based on published studies and product labeling.

Agents targeting other pathways demonstrate clinical profiles that either require far more frequent injections per year to achieve similar clinical benefit as in the case of Dupilumab or demonstrate significantly lower treatment effects in the context of twice-yearly dosing as seen in published trials with Depemokimab, a YTE modified anti-IL-5.

Before I turn the call over to Aaron to review the trial results in further depth, I'd like to provide a bit of context about Upstream Bio about our molecule verekitug and about CRSwNP. Upstream Bio is a clinical stage immunology company, and our initial focus is on severe respiratory diseases. We are developing verekitug, the only known antagonist of the TSLP receptor. Verekitug's unique pharmacology has been evaluated in preclinical and early clinical studies and is characterized by rapid, complete and sustained occupancy of the TSLP receptor for up to 24 weeks after the last dose.

Our corporate strategy is aligned with our focus on severe respiratory diseases and is designed to maximize the value of verekitug across multiple indications with unmet need. VIBRANT, our Phase II trial in CRSwNP is now complete. VALIANT, our Phase II trial in severe asthma is on track to report top line data in the first quarter of 2026, and VENTURE, our Phase II trial in COPD is actively enrolling participants. TSLP biology also supports future expansion into other therapeutics, including other therapeutic areas, including dermatology and GI.

Verekitug targets the receptor for TSLP and blocks its assembly. It is the only agent known to do so and inhibiting TSLP has been shown to reduce both type 2 and non-type 2 inflammatory processes, providing broad anti-inflammatory effects. The TSLP receptors both expressed and renewed at lower rates than the TSLP ligand and our data has shown verekitug by virtue of targeting the receptor is approximately 300-fold more potent than Tezepelumab, an antibody targeting the TSLP ligand. On the basis of preclinical and clinical data supporting verekitug's highly potent inhibition of the TSLP receptor, our clinical programs have been designed to test the translation of this potency to both dosing interval and efficacy in CRSwNP, severe asthma and COPD.

CRSwNP is a TSLP driven upper airway inflammatory disease, which causes significant and disabling symptoms. These symptoms have a major impact on quality of life and severe forms of the disease can require recurrent surgery and courses of systemic corticosteroids, which can cause substantial morbidity in the form of osteoporosis and other complications. Because of overlapping disease biology, the majority of patients with CRSwNP will also have comorbid asthma. In recent years, novel biologics have been approved for the treatment of CRSwNP and while sales of these therapies in CRSwNP now exceed $1 billion annually, they are projected to grow in coming years, driven by the arrival of additional agents and expanded use in both surgery experienced and surgery-naive patients. Our market research indicates a high degree of interest among both allergists and ENTs for the use of biologics in this indication with a strong belief that TSLP inhibition could be a highly efficacious mechanism of action in this disease.

With that introduction, I would like to turn the call over to Dr. Aaron Deykin, Upstream's Chief Medical Officer and Head of R&D, to take us through the details of the top-line VIBRANT Phase II data.

Thanks, Rand. First, let's start by reviewing the VIBRANT study design. VIBRANT was a Phase II randomized, double-blind, placebo-controlled parallel group clinical trial designed to assess the efficacy and safety of verekitug in adult patients with moderate to severe CRSwNP. Eligible participants who were enrolled from the U.S. and 4 European countries had a documented history of nasal polyps requiring prior NP surgery or systemic corticosteroids in the past 24 months, had a bilateral endoscopic nasal polyp score at screening of at least 5, had ongoing CRSwNP symptoms despite standard of care treatment and had a nasal congestion score or NCS of at least 2 during screening. 81 participants were randomized in a 1:1 allocation to either 100 milligrams of verekitug or placebo subcutaneously administered once every 12 weeks over a treatment period of 24 weeks.

The VIBRANT trial was designed with widely accepted and standardized endpoints. The primary endpoint was the change from baseline in nasal polyp score, NPS at week 24. This primary endpoint has been used in several registrational trials for other biologic treatments for CRSwNP. The sample size provided greater than 85% power to detect a clinically meaningful treatment difference of 1.5 points on the NPS. Secondary endpoints included the NCS, sinus opacification on CT scan evaluated using the Lund-Mackay score or LMK. Total Symptom Score, or TSS, Difficulty with Sense of Smell Score or DSS and percentage of participants requiring systemic corticosteroids or nasal polyp surgery. Safety was carefully monitored and characterized in collaboration with an independent data monitoring committee.

Now reviewing the disposition of the ITT population, 81 patients were randomized with 40 randomized to receive placebo and 41 randomized to receive verekitug, providing ample statistical power to detect a meaningful change in the NPS over the 24-week treatment period. We do note one subject was a screen failure but was randomized in error to verekitug and was not dosed. All participants in the verekitug arm completed treatment and 5 subjects, all in the placebo group withdrew from the study. As a result, the discontinuation rate from this study was lower than anticipated with 75 participants or 93% of those enrolled completing the trial.

Now as we look at the baseline characteristics for the participants in this study, we see that they were consistent with the design and were generally balanced across the dose groups. We did note a slightly higher baseline eosinophil count in the placebo group, but do not believe this affects the interpretation of our results. Furthermore, as we'll detail further shortly, the characteristics of the population studied in VIBRANT are similar to those included in recent studies of other biologics for CRSwNP.

Now considering safety, we're very pleased to see that verekitug was generally well tolerated with a profile consistent with that we've seen in our previous studies. Overall, the incidence of treatment-emergent adverse events, or TEAEs, with similar across the treatment groups and TEAEs related to study treatment occurred more frequently in the placebo group. No severe AEs or serious AEs were reported and no grade 3 or greater injection site reactions were observed in this study. Now the most common treatment-emergent adverse events that is events occurring at 5% or greater in the population in this study were up for respiratory tract infections, sinusitis, nasopharyngitis, nasal polyps and headache. All of which are associated with CRSwNP itself.

Now turning to efficacy. We are very pleased to report that in the VIBRANT study, verekitug administered just once every 12 weeks had clinically and statistically significant effects at the end of this 24-week study on the primary endpoint of endoscopic nasal polyp score as well as key secondary endpoints, including the nasal congestion score. Specifically, we observed at 24 weeks of placebo-corrected reduction from baseline in NPS of 1.8 points, in NCS of 0.8 points, in the LMK of 8 points, in TSS of 4.3 points and in DSS of 0.9. Now consistent with FDA guidance, these results are based on the observed data without consideration of intercurrent rescue systemic corticosteroid use. And in this regard, the estimates of treatment effects are considered more conservative than results using an approach with sensors data observed data systemic corticosteroids. It's an important point to keep in mind, as notably, this trial also demonstrated a significant 76% reduction in the need for steroids or surgery in the study participants.

Now considering the trajectory over time in NPS and NCS, we again see that at week 24 for verekitug treated patients achieved a clinically meaningful 1.8 placebo-corrected reduction in NPS change from baseline and a 0.8-point placebo-corrected reduction from baseline in NCS. And again, I'd highlight here that these do not take into account or adjust for the impact of rescue systemic corticosteroids. Looking at the NPS, we see that the majority of the effect is apparent at week 12, although we do see continued improvement to week 24 and as it does not appear that our plateau in NPS has been reached, a study of longer duration, such as we plan for Phase III, will clarify the potential for additional effects of verekitug on NPS over time. With NCS, we observed reductions occurring as early as 2 weeks, where a nominally statistically significant difference between groups was first seen.

Importantly, this effect was maintained throughout the dosing interval and these observations are consistent with the rapid and sustained suppression of inflammatory biomarkers that we have seen in our prior trials. When we analyze the data in clinically relevant subgroups of patients, we also observed that the effects of verekitug on NPS were robust. Our analysis shows that point estimates for the placebo-corrected NPS over 24 weeks are consistently documented favoring verekitug in these subgroups.

Now when considering the VIBRANT trial in the context of other studies completed with other biologics, it's first important to compare the population study. As demonstrated here, the baseline characteristics of the VIBRANT participants are very consistent with those enrolled in other studies, including age, disease duration and severity, presence of comorbid asthma and the need for prior surgery. We do note slightly higher baseline eosinophil counts as compared to some trials as well as a lower rate of recent treatment with systemic corticosteroids. We believe the latter may reflect the change in CRSwNP management driven by an increased use of biologics versus systemic corticosteroids in recent years, but overall, I do not believe that either of these aspects meaningfully affect the interpretation of our results.

Now putting our results in the context of others and with the caveat that this comparison is for illustrative purposes only, verekitug, again, administered every 12 weeks equivalent to 4 times per year demonstrated improvements in both absolute and placebo-corrected endoscopic nasal polyp score at 24 weeks that are generally consistent with those seen with Tezepelumab, which requires administration every 4 weeks equivalent to 13x per year to achieve this effect based on published studies and product labeling. Agents targeting other pathways demonstrate clinical profiles that either require far more frequent injections per year to achieve a similar clinical benefit as compared to verekitug. For example, in the case of Dupilumab or demonstrate significantly lower treatment effects in the context of twice-yearly dosing as seen in published trials of Depemokimab, a YTE modified anti-IL-5.

So in summary, verekitug administered just once every 12 weeks, have clinically and statistically significant effects at the end of the 24-week study on the primary endpoint of endoscopy nasal polyp score as well as key secondary endpoints, including the nasal congestion score. Remarkably, this trial also demonstrated a statistically significant impact of verekitug on the need for steroids or surgery in the study participants. As we've seen in previous studies, verekitug was also generally well tolerated with no serious adverse events reported. These trial results further extend the consistent body of preclinical and early clinical data from our development program, which together suggests the potential for verekitug to deliver a meaningful clinical benefit at a substantially reduced dosing interval compared with other biologics.

Taken together, the data to date reinforce our belief that the differentiated profile we've observed is driven by verekitug's unique mechanism of action. So we're very pleased with these data and look forward to maximizing the impact of verekitug for the treatment of severe respiratory diseases.

And with that, I'd like to now turn it back to Rand.

Well, thank you very much, Aaron. As I hope you can all hear we are very excited about the positive trial results we're reporting today. How are we interpreting these data? First, verekitug delivered significant effects on the primary and key secondary CRSwNP endpoints in this VIBRANT trial. The clinical activity is delivered at a differentiated dosing interval of every 12 weeks and importantly, verekitug's safety profile continues to be favorable. Verekitug's the first extended dosing TSLP agent to demonstrate this profile, which is uniquely driven by potency rather than antibody engineering which simply extends drug half-life without altering potency.

Given the role of TSLP and other respiratory diseases, including asthma and COPD, these data support further development of verekitug in multiple indications with substantial unmet need and commercial opportunity. As I mentioned earlier, TSLP drives inflammation in all of the diseases in which we are currently testing verekitug, along with others, and these data give us confidence that verekitug may also demonstrate meaningful clinical effect in severe asthma and COPD. Our rationale for testing verekitug in both CRSwNP and severe asthma has centered on a number of data points.

First, the TSLP plays an important role in driving inflammation in both diseases; second, that many patients will suffer from both indications at the same time and third, by the fact that biologics targeting not only the TSLP ligand, but also the IL-4 receptor alpha, IL-5 and IgE all have demonstrated efficacy in both indications. In general, the relative magnitude of effect of these agents on NPS in CRSwNP studies is commensurate with the magnitude of their effect on reducing exacerbations in severe asthma. Taken together, these points, along with the VIBRANT data in CRSwNP increase our optimism that the clinical benefit of verekitug in severe asthma will be at the very least similar to that observed in the registrational studies of Tezepelumab and Dupilumab will also potentially requiring treatment only 2 or 4 times per year.

Very soon, in the first quarter of 2026, we will add to our understanding of verekitug in this context with the planned top line data release of our randomized, placebo-controlled dose-ranging Phase II trial in severe asthma.

As we conclude, on behalf of the entire team here at Upstream Bio, I would like to thank the participants who enrolled in VIBRANT, along with our clinical trial investigators and site staff who collaborated with us to execute this important trial. Your support and participation have helped us move an additional step forward in the development of a potentially new treatment option for CRSwNP, and we hope for other respiratory diseases as well. And lastly, to our outstanding team here at Upstream Bio, I appreciate all of the work and dedication you have put in to get us to this point.

Thank you. And with that, we are happy to take questions. Operator?

[Operator Instructions] Our first question comes from Tess Romero with JPMorgan.

Congrats on the data here. So the first one is -- to what do you attribute the stat sig results you found across various secondary endpoints beyond nasal congestion score, which I think came in ahead of your expectations? And second, looking ahead, what are your preliminary thoughts around the dose used in the study? And where you think you could go from a dosing standpoint and the indication, do you think you might explore Q 24 weeks here? And why or why not?

Thank you very much. We appreciate the question. I think as we've mentioned in this -- in our narrative this morning, potency is what drives all of this. This is the single defining feature of verekitug. And so at a very high level, it is the attributes of the molecule, the fact that it targets a receptor and the aspects of turnover and refresh of the receptor versus the ligand that we think drives not just the top line, sort of primary and secondary endpoints, but really everything that we've shown today.

Sure. Tess, it's Aaron. And thanks for your question. Really to extend on what Rand said, I think that the very clear results with efficacy demonstrated across a range of endpoints begins with the molecule itself and the fact that it is efficacious, at least as demonstrated in this Phase II study. I'll also point out that a set of results like this really can only occur with a very well conducted study, where variability is reduced and you enroll the population that you intend to. And I think that we've been quite pleased that that's what we've been able to achieve.

In terms of the dose considerations, our data here really do validate our model-based understanding of the PK and ultimately, the pharmacodynamics of the molecule. In particular, we do not see any attenuation of treatment effect at the end of the dosing interval. And that really suggests to us that with Q12 weeks, we certainly are controlling disease symptoms very well and completely throughout the interval. That being said, and especially given the validation we have of our PK/PD modeling from this study, there is a substantial probability in our mind that every 24-week dosing could be effective.

However, that's really going to be proved out and informed by the coming results from our VALIANT asthma study where we're doing much more complete dose ranging. So ultimately, we expect to get those results and then contemplate a unified dose to move forward with in both indications. So we'll be really looking very carefully at those data that are going to be coming in the first part of next year.

Our next question comes from Yaron Werber with TD Cowen.

Congrats on really solid, solid data. I mean, both on efficacy, I mean, hitting stat sig and steroid use and surgery in a small Phase II is a big deal. Maybe just a question, Aaron. You mentioned -- so Teze, is I think the drug that you're sort of alluding to in the Phase III in the WAYPOINT study, they did not exclude patients that had steroid use. Have you had sensitivity and you did, so you took a more conservative approach. Have you had a chance to run some sensitivities? What would happen to the NPS and potentially NCS scores if you use the same endpoint? And then I have a follow-up as well.

Okay. Yes, Yaron, thanks for the question. And yes, we did use the statistical approach that's recommended by FDA in their guidance document, perhaps that might have been conservative in this Phase II study. But nevertheless, that is what we did. We do have a sensitivity analysis with respect to the NPS, the primary end point taking an approach that's consistent with what some others have done, which is to sensor the data after a patient is exposed to rescue corticosteroids. And when we do that, we do add an additional 0.1 to our treatment effect. So going from 1.8 to 1.9 on treatment effect on the NPS. Additional sensitivity analyses on the other endpoints are not available right now at the top line point that we are.

Okay. And then just a quick question on -- so there's no plateau in the NPS endpoint at 24 weeks. And so do you -- I know -- release everything at a medical meeting soon or at some point in the future. What are the biomarkers showing you on Fino is relating to the half life? I'm kind of wondering if you treat for longer, you'll have even a better effect as the other drugs did.

Yes. So we can only speculate at this time. I do think pretty consistently looking at data in this indication, you do see accumulation of treatment effect beyond 24 weeks in multiple agents. So I think that that's a reasonable assumption that when we conduct a longer trial, we will see some additional treatment effect on the NPS. In terms of the biomarkers, we don't have biomarker available to share at this time. And certainly, we're very eager to see those data when they come in, and we will share them at a medical meeting once we have them. But in some, yes, we do anticipate greater treatment effects in longer studies. And -- but we'll have to wait to see if that actually occurs when we do those studies.

Our next question comes from Yasmeen Rahimi with Piper Sandler.

Congrats to the great data, and thank you again for a very thorough presentation. I guess question number one is -- you did a really nice job comparing the NPS scores across different subgroups. Could you maybe talk about if Teze has done a similar exercise and whether they found a similar response rate across all subgroups? If you could just talk about the differences there. That's question one. And then question two is given this data, how do you think -- our favorite question, what the bar for success here is for your asthma study that's reading out in 1Q '26, and I'll jump back in the queue.

Yes. Okay. So with respect to comparing subgroup analyses across trials, I think that, that's always a sort of a double extrapolation exercise and probably something that has to be done really with a lot of caution, especially because with Tezepelumab, the subgroup analyses were all done at their 52-week data. Nevertheless, I would say that, generally speaking, there doesn't appear with this mechanism to be a subgroup of patients that doesn't respond, and that's been a consistent finding with our subgroup analyses as well. Yes, do you just mind repeating the other question about the asthma data? I just want to make sure I get the question right.

And just saying maybe help us understand what your expectations are now that you have seen this data on hand with the durability.

Sure. Absolutely. So thanks. And I think that Rand's slide that he talked to, which, of course, is a schematic, but it's a schematic representing our belief. We believe that given the efficacy that we've demonstrated in CRSwNP that we interpret as meeting or potentially slightly exceeding that scene with Teze would indicate that, that's the type of efficacy in asthma that we should see.

And yes, thanks again for the question. I think we are sitting on a really consistent body of data, starting with preclinical assays, moving into our multiple ascending dose trial in patients with asthma that demonstrated proof of concept and now these data, they really illustrate the potency of this molecule. And I think we've kind of held our hypothesis back a little bit in NP just to understand what dynamic range could be. But I will just remind you of the data from our MAD study that suggests that our effect on exhaled nitric oxide and blood eosinophils are really quite substantial and potentially substantially greater than many other agents. So I think we feel pretty good.

Obviously, we're doing the trial, and we have equipoise until we see the results. But that statement about feeling good about meeting or exceeding efficacy on the therapeutic front and doing that with either twice yearly or 4 times a year dosing, if we can hit some combination of those outcomes, that's going to be, we think, a very strong and competitive product profile.

Congrats again.

Our next question comes from Matthew Phipps with Blair.

Congrats on a great first Phase II readout with verekitug. I was wondering if you could give us a breakdown in the control or between patients who had surgery versus rescue steroids and it was 25% across all patients. And then do you have a survival analysis on the timing of those events for both arms? Just curious thinking about how that effect might grow between verekitug and placebo out to 52 weeks on that endpoint.

Yes. So Matt, it's Aaron. Thanks so much for the question. With respect to the first part in terms of the breakdown of steroid -- systemic steroid exposure versus surgery, only one subject had surgery. And therefore, the issues that I was highlighting about the impact of systemic corticosteroids are important since the vast majority of the cases of surgery or steroids were in fact, steroids in this trial. We don't, at the current time, have a survival analysis or a time to analysis of the surgery or exposure to corticosteroid events, that's coming. I could imagine that, that difference between placebo and treatment might accumulate over time as more time at risk for these events will increase with exposure. So that's something, of course, that we can only speculate on, and we need data from a larger study to confirm, but that's probably a fair guess.

A quick follow-up. I know 60% of patients in this trial had asthma, a lot of overlap in the indications. I was wondering if you've had a chance to do any subgroup analysis on those patients or look at any other maybe more asthma-specific markers in that population.

Yes. Absolutely. Very important question. We're very eager to see those data. Those were not prioritized as part of our top line, but they will be coming and we'll be looking at that and disseminating what we see as soon as possible at an upcoming meeting.

[Operator Instructions] I'm showing no further questions at this time. I would now like to turn it back to Rand Sutherland, Upstream Bio's CEO for closing remarks.

Thank you, and thanks to everyone for taking the time to join us today to hear our data and for questions. We look forward to sharing additional progress with you as we move forward. And with that, we'll end the call. Thank you.

This concludes today's conference call. Thank you for participating. You may now disconnect.