Team from Upstream Bio. With me on stage is Rand Sutherland, and Mike Gray, Company CFO, is here in the audience. Rand, I thought it would be helpful for you to start with the vision for Upstream and where you're taking the company. Sure. Well, Dave, first thank you for having us. We're always thrilled to tell the story. Upstream Bio, I think as many people know, is a clinical stage company focused on the development of a monoclonal antibody antagonist of the receptor for TSLP. That molecule is called verekitug. Now in two indications in placebo-controlled phase II trials, we've generated data that really reinforce the pharmacological profile of this molecule. That profile is really marked by substantial efficacy and the ability to deliver the drug at extended dosing intervals, all of that being driven by potency rather than by any modifications to the molecule itself to extend the half-life. About a month ago now, we read out the data from our phase II severe asthma trial called VALIANT. Those data again, really reinforce the profile of this molecule as one that can deliver efficacy that meets or exceeds that of other marketed products in the space, and again, does so at quarterly dosing. We are now deep in the throes of analyzing these data, understanding, you know, how they've helped us learn even more about the molecule, understand what we will be doing for dose selection for phase III, and really working hard to de-risk this program as much as we can, so that we, as we move forward into phase III, we really have a strong understanding of how this molecule will deliver our aspiration, which is to deliver outstanding efficacy with far less frequent dosing than currently marketed products. Excellent. Could you just highlight some of the figures, just remind us about that efficacy that you described in the recent results, and then also talk a little bit about the efficacy in patients with different eosinophil counts? Sure. The approach that we took in severe asthma with our phase II trial was to test three different dose regimens. A high, a medium, and a low dose. The high dose regimen being 100 mg Q12 weeks, the medium dose being 400 mg every 24 weeks, and then the low dose being 100 mg every 24 weeks. The intent of this trial, as is typically the case in phase II development in asthma, is to really understand, first of all, is the molecule behaving as you would have anticipated from sort of earlier clinical studies? Is it behaving as you would predict from what we understand about the biology? You know, have you been able to emerge from the trial with really a robust and broad set of data that again allow you to make the kinds of decisions you need to make to move forward in phase III. What we demonstrated across the board was statistically significant reduction in the annualized asthma exacerbation rate, actually in all three dose regimens tested. Our sort of highest likelihood of success, and I think our sort of, quote, "base case" profile here was to deliver Tezspire-like efficacy at quarterly dosing, and we did exactly that in the high dose regimen of 100 mg Q 12 weeks. You know, the magnitude of the reduction in asthma exacerbations there was 56%. That was statistically significant with a very robust P value. We delivered improvements in both lung function as measured by FEV1 and biomarker suppression as measured by the percent change in exhaled nitric oxide of a magnitude, again, very similar to what's out there on the market today. As we move forward into the medium and the low doses, what we saw was some evidence of dose ordering, and that's again, exactly what you wanna see. You wanna see your efficacy, start to fall off, particularly as you get to lower doses. One of the things that we also learned here is that the pharmacology of the molecule is likely, we think, to be most efficacious at quarterly dosing. We know from market research and a lot of work that we've done, that if you can deliver a product with outstanding efficacy, and that's not just with asthma exacerbations, but with lung function symptoms and biomarker suppression, and do that with quarterly dosing, you actually have a very valuable profile. We've learned a lot from the phase II trial. There again are a whole host of data here, hundreds of patients of worth of data that are gonna inform our dose selection for phase III. Our goal here is to really push the dose as high as we can and choose the right dosing interval so that we can deliver a maximally differentiated medicine. Excellent. Obviously you're not ready to disclose anything because you haven't made any decisions. How are you thinking about the possibility of pushing the dose in phase III? Yeah. I think... I mean, again, as I mentioned at the beginning, the pharmacology of verekitug is really notable for extreme potency. It's about 300 fold more potent than tezepelumab. You can spend that potency in one of two ways. You can spend it by driving efficacy, or you can spend it by extending the dose interval, or you can try to find the sweet spot. Of course, that's what we're trying to do. You know, if you look at the data, these are in our presentation deck, it's interesting in that at the first time point measured, both with regard to lung function and biomarker suppression, the maximal degree of efficacy is actually achieved, as you might expect, with that 400 mg dose. If you look over time, what you see is that the Q24 week dosing, twice-yearly dosing, actually starts to be marked by a little bit of loss of effect with both of those endpoints towards the latter part of that dosing interval. Interestingly, with the 100 mg Q12, that line is essentially flat. What we're trying to do, and we're doing it in a more sophisticated way than I'm describing by just looking at a couple of dot plots, is to take that efficacy curve over time, keep it as robust and unwavering as possible, and then push it as high as possible. We're asking again, what is the right dosing interval? I think there's, you know, evidence that Q12 weeks is the one in which we get, again, most robust and consistent efficacy, and then asking, could we push an even higher dose to deliver even greater efficacy? We're well underway doing that. I think here in the coming weeks, we should be able to communicate more as we learn more from the work that we're doing to analyze the data from this trial. Got it. Excellent. It sounds like you're gonna be, you know, conveying something relatively soon in terms of go forward for phase III. I think we've again, we've learned a lot. You know, one of the challenges about being a small public company is that the data that you get in real time become quite material, and, you know, you sort of have to get those out there. You know, you need more time to really fully analyze the data. I'd say that, you know, if you look at sort of normal timelines for analyzing these types of studies and making decisions, you know, often they are on the order of several months to quarters. We're moving as quickly as we can. A, because we wanna continue to progress this molecule and, you know, keep timeline advantages that we believe we have, but also so that we can communicate and help people understand what it is that we're doing. Anything that we say before we align with regulators, of course, is highly forward-looking. We do think there will be additional information to convey with sort of the final degree of alignment coming after we discuss this with regulators and hopefully emerge in Q3 of this year with a clear path forward. Excellent. Makes a lot of sense. Yeah, because what you decide is not likely to be a, a real concern or question for the regulators because it's within the parameters of what you've assessed to date. Yeah. I won't speak for the regulators, but I will, on that last point, just pick up on, you know, we are working within the confines of the data that we've generated. Yep. That's actually why we've developed this molecule the way we have. You know, it's far more typical to go through an extended, you know, phase I, phase II dose-ranging type approach in these diseases so that you really understand your molecule, get the dose-ranging data to help you understand how you can leverage the biology, and that's why we've taken the approach that we've taken. Makes sense. Okay. Then just pivoting to the long-term extension study. Could you comment on that, please? Sure. We've had really a strong degree of enthusiasm for patients continuing to be on verekitug, and so we've had a very high rate, over 90%, roll over from the phase II trial into the long-term extension study. Now, in our long-term extension study, we are actually taking patients, and if they were not allocated to the higher than medium dose, so the low dose or placebo, those two regimens, they actually get re-randomized to either the high or the medium dose. Not only are we getting extended follow-up on the patients who were allocated to those regimens in the phase II trial, we're also generating new data, and, you know, some potentially step-up data from, you know, our phase II to LTE extension as well. We actually have the ability to measure pharmacology in those patients. All of those data go into our pharmacology model. You know, I would anticipate that we will continue to learn even more about the long-term efficacy of the drug, its long-term safety, importantly, and the pharmacology as well. Excellent. Before I continue on with questions, just wanna see if any others in the audience have any questions. All righty. I'll keep rolling. Before we go into COPD, I did wanna ask about, within asthma, just, you know, how you're thinking about emerging competition from, you know, companies like Generate, which came public recently, and also Glaxo with their long-acting TSLP. Any high-level comments that you could provide? I think there are two universes of competitors that we look at. The first are, you know, the numerous set of ligand-targeting antibodies against TSLP. We're the only drug targeting the receptor. There are many going after the ligand. Some are short-acting. Some have taken advantage of Fc engineering to extend the half-life. There are also, you know, multi-specifics that are out there. I think on the long actors, you know, I made a comment about how we've developed our drug and how we are going into end-of-phase II negotiations with over 500 patients' worth of data. We really understand the pharmacology of our molecule. We think that's really important from the standpoint of making the right choices for phase III. We think it's the right decision and the right thing to do because you really wanna understand the safety profile of your molecule. You know, we really wanna come forward with a proposal for studying this in phase III that not only makes regulators, you know, that allows strong conversations with regulators, but also makes physicians and patients, investigators and patients, wanna participate in this study. You know, we think that that's the right way to progress a program and de-risk it. I think that not doing that and, you know, heading straight from phase I to phase III, as some have done, is associated with, you know, a higher degree of risk than we would wanna carry forward. I think, you know, the other thing is we really want to deliver maximal efficacy at as extended of a dosing interval as we can. We're gonna, you know, be able to understand what attributes of the molecule allow us to deliver that profile heading into phase III. I think, you know, for those who are, you know, in phase II or going from phase II to phase III, we look forward to hearing more about the pharmacology of those molecules and understanding what it is they, you know, might be able to bring to the table. It's a great thing for patients to have a lot of different options. You know, for us, we wanna continue to leverage the unique attributes of our molecule. We aspire to bring the best profile possible to the market, and we wanna continue our strong history of execution and timelines, so that we can continue to do this in an as advantageous of a way as possible when it comes to market entry. Excellent. Why don't we pivot to the market for biologics for asthma? Could you talk about that and where that's headed just to contextualize, you know, the market that you'll be competing in longer term? Sure. I think from the beginning, we've really been contextualizing ourselves against the marketed products. And why do I say that? Well, you know, we could talk about the bispecifics in a minute, but, you know, we have kind of always really seen the universe of therapeutics in this space as converging around a limited set of targets. You know, a year ago, we might have thought that IL-33 was gonna be out there as competition. We might have thought that OX40 ligand were gonna be out there. I think you've seen a lot of sort of the novel targets start to fall away. You know, the field is now converging around TSLP, IL-4, IL-13, IL-5, and IgE really as the target space. The question becomes, well, how do you innovate, you know, in that relatively limited set of targets? you know, we've talked a lot about how we think verekitug is innovative and how its potency will translate to a differentiated clinical profile. But that differentiation has to be meaningful. It can't just be extended dosing without advantageous efficacy. you know, it's our belief that what the market has told us over time is that novel entrants can come in and can drive, it could be quite successful. I mean, just look at Tezspire's launch for evidence of that. That success is driven, first of all, by being differentiated, either in terms of efficacy or eligible patient population or both. You know, you need to have that kind of differentiation in hand to come in and compete against the likes of a Tezspire or Dupixent or the IL-5. We know that we need to push efficacy as high as possible. We know convenience will add a lot. We know actually that quarterly dosing is viewed very favorably, and that there's limited uptake that comes from going from quarterly to twice-yearly dosing, and that if there's any diminution in efficacy, there's actually loss of that preference very quickly. That's the universe that we wanna come in, and the reason we wanna do that is, again, because we think that we can drive penetration, we can increase overall share and do it, you know, again, with a unique and differentiated profile. Right now in the bispecific or multispecific front, there's not yet evidence that multispecificity is better than good monospecificity. There'll be more to come, obviously, here even in the first half of this year, we think, with, you know, a major bispecific program that's, you know, underway at another company. you know, we'll follow that very closely, but right now, again, feel that we're in a very strong position. Excellent. Excellent. Turning to the COPD opportunity, the company disclosed that enrollment was over 60% in the VENTURE COPD trial. In the wake of the VALIANT results, if you could just talk about how you know, you're thinking about potentially making changes to that COPD study as well. Sure. Maybe I'll just start with a little refresh on the ambition in COPD. Okay. You know, it's been very clear, and this has now been validated, you know, through, I think, you know, IL-5, IL-4, IL-13, and even the early work that the tezepelumab program has done, that modulation of Type 2 inflammation, at least in the subset of patients with COPD, is a tractable, therapeutic option. You know, we saw the phase II data from tezepelumab in COPD, and we're very excited about those as, again, building and sort of offering the opportunity for yet another Type 2 immunomodulator to have a potential benefit for these patients. What it seems is pretty clear to us is that, you know, like in asthma and, CRS with NP, you know, the biology suggests that the patients who are most Type 2 in their inflammatory phenotype are the ones who are gonna respond most to these drugs. For that reason, there seems to be a pretty clear signal that an eosinophilic phenotype in patients with COPD is the population in which there's likely to be the greatest degree of effect. That's the group that we are testing this drug in. We actually have our primary analysis, you know, planned in the eos 150 and up group there. You know, really see that as a potential opportunity to leverage the biology, leverage the potency of verekitug, and, you know, to try to have a significant positive outcome there. Now, we started that trial testing the high dose and the medium dose from our severe asthma study. Now that we have these new data from the severe asthma readout, you know, we will have to think about whether or not if we do, say, decide to push dose or do something different than what is currently being studied in the COPD program, how we might introduce that into our ongoing thinking for that program. I think it's a little too early to be specific there 'cause we are, you know, we need the data for dose selection before we can really start to contemplate all the, you know, potential things we might do there. Excellent. Okay. That makes a lot of sense. Going back to Tezspire's COPD trial results, so that disappointed. Could you comment on that and, you know, how you see the opportunity for verekitug? Yeah. I mean, I think our view of the Tezspire COPD data were maybe slightly different. I mean, that was a, you know, in these studies, you really have to do very large, you know, sample sizes, really long periods of follow-up to be able to get a signal. I don't think that, at least from our interpretation, we ever thought that that trial was powered or designed to be sufficiently powered to detect an effect in all comers. But what we were very excited to see was the fact that in that eos 150 and up subset, there actually was evidence of a significant reduction in COPD exacerbations. Back to this point of sort of, again, Type 2 inflammation driving responsiveness to these drugs across the board. You know, in COPD, which is probably the most heterogeneous of the inflammatory phenotypes of the, in the three diseases that we're testing, again, you wanna enrich for that higher inflammation population. We saw actually those data as a clear reason to prosecute our program in COPD as well. Okay, that's very helpful. What is the target product profile that you're aiming for in COPD? Maybe I'm getting ahead of myself, but potential commercial positioning. Yeah. I think you can, you know, although they are different diseases, in general, what you are trying to achieve clinically in COPD is very similar to what you're trying to achieve in asthma. You want to prevent exacerbations from happening. We know that exacerbations not only are events that drive a lot of patient symptomatology and burden, they also drive a lot of healthcare utilization, and particularly in COPD, they are likely accelerants of disease progression as well. There are a lot of reasons to try to reduce COPD exacerbations. At the same time, you would like to be able to control symptoms, and to the extent that you can, improve lung function as well. How exactly robustly you can do that in COPD is, you know, I think still a bit of an open question. Remember that in both COPD and asthma, participants in these trials and patients who get these drugs already are on inhaled, maximal inhaled pharmacology. They're getting, you know, inhaled corticosteroids, and they're often getting 2 long-acting bronchodilators as well. That, you know, background therapy has to be. You have to show efficacy on top of that. You know, our profile in both cases would be reduction of exacerbations. The profile that we're aiming for would be reduction of exacerbations, improvement of lung function, and improvement of symptoms, all with, you know, results that are both clinically and statistically meaningful and, you know, important for payers as well. Excellent. Maybe we could just turn to the event path. Clearly you'll provide an update, you know, ahead with respect to phase III plans for verekitug in asthma, and then you'll meet with the FDA and provide more details on that in the third quarter. Could you talk about, you know, additional events to watch for the company over the next year or two? Sure. I think, you know, the next logical set of catalysts after, you know, finalizing regulatory negotiations is phase III start. We would move as quickly as possible to have those programs, and when I say those, I'm talking phase III, both in severe asthma and CRSwNP, to have those up and running by the beginning of next year, end of this year, roughly. I think whatever, you know, when we finalize our path forward in terms of COPD, we'll be able to give a little bit more precision there, just about timelines and potentially catalyst path there. That's not something that we have really commented on yet beyond the fact that we're 60% enrolled or more in that program, and so we should be able to provide some more precision there as well. Okay. Very good. Could you talk about CMC, and device development, please? Sure. You know, drug substance and drug product development have been a key focus of our work since the very early days. We have done a lot of work over the last four or so years to improve our formulation. We now have a highly concentrated formulation of 200 mg/mL. That puts us in a position where we can deliver our highest dose of 400 mg in 1 single 2 cc injection. That's important both in terms of, you know, making it as comfortable for patients as is possible, and also practically it's important because that's the volume that commercially available autoinjector platforms can deliver. Our ambition would be to, and we've made the investments not only in the CMC but in, you know, device development as well, to be able to, launch, you know, with an aspiration to launch with a, an autoinjector delivering, you know, in a single injection the dose that we would choose to commercialize. Excellent. Are there any additional steps or decisions you have to make? Have you decided on device, et cetera? I mean, I guess it's commercially available, so it's... Yeah ... straightforward, but... Straightforward might be pushing it a little bit. These are always a little bit tricky things to do in the end, but, yes, we are working with a commercially available platform that is already on the market that other drugs use. There's little in the way of new technical innovation there that is required but, you know, the marriage of the drug substance with the device itself is, you know, it's work, and it's actually technically complicated work. We've got the right partners to help us with that. We know what the regulatory path is, and we have all the steps laid out to be able to prosecute all of that while, you know, getting to the market with that device. Would that be done in parallel with conducting phase III then, or would you have it ready by the end of this year? No, it will not be. That will not all- Okay ... be ready by the end of this year. It's very typical to do all of these steps in parallel with- Got it. ... the prosecution of your phase III. Yes, that's what we'll be doing. Okay. Perfect. I think we're gonna be running out of time soon. Could we just close out with the company's latest with respect to its cash position and the runway? Sure. We ended the last quarter with $341 million of cash. You know, we've signaled that that provides runway through 2027. That provides runway through 2027 as we are prosecuting this Max plan. It allows us. It's gotten to this point where we've delivered two separate phase II programs. It's enabling all the phase III preparations and the initiation of phase IIIs in severe asthma and CRSwNP. It's allowed us to continue to move our phase II program in COPD forward. It's enabled all this CMC and device development work as well. Excellent. Well, congrats on the progress. Thanks so much again for being here with us.